Quinoline compounds as modulators of rage activity and uses thereof

ABSTRACT

and wherein Cy, R1, R4a, R4b, and n are as described herein. The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, diabetes complications, inflammation, and neurodegeneration, obesity, cancer, ischemia/reperfusion injury, cardiovascular disease and other diseases related to RAGE activity.

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority under 35 USC § 119(e) from U.S.Provisional Application Ser. No. 62/323,983, filed Apr. 18, 2016, whichapplication is herein specifically incorporated by reference in itsentirety.

GOVERNMENTAL SUPPORT

This invention was made with government support under grant1R24DK103032-01 awarded by the National Institutes of Health. Thegovernment has certain rights in the invention.

FIELD OF THE INVENTION

This invention relates to quinoline compounds capable of modulating thereceptor for advanced glycation end products (RAGE) activity.Specifically, this invention relates to quinoline compounds capable ofmodulating the interaction of RAGE and its ligands, and uses of suchcompounds to treat diseases or conditions related to RAGE activity. Moreparticularly, the quinoline compounds may be used to treat diabetescomplications, inflammation, and neurodegeneration, obesity, cancer,ischemia/reperfusion injury, cardiovascular disease and other diseasesrelated to RAGE activity. Also encompassed herein are compositions ofquinoline compounds, pharmaceutical compositions of quinoline compounds,and assays and methods for using same to identify compounds capable ofmodulating RAGE activity.

BACKGROUND OF THE INVENTION

The receptor for advanced glycation end products (RAGE) is a multiligandcell surface macromolecule that plays a central role in the etiology ofdiabetes complications, obesity, inflammation, cancer andneurodegeneration. The cytoplasmic domain of RAGE, C terminal RAGE orctRAGE (RAGE tail) is critical for RAGE-dependent signal transduction.As the most membrane proximal event, DIAPH1 (also known as mammalianDia1 or mDia1) binds to RAGE and is essential for RAGE ligand-stimulatedphosphorylation of kinases and cellular properties such as AKT and cellproliferation/migration of smooth muscle cells; activation of cdc42 andracl in smooth muscle cells and transformed cells; and upregulation ofearly growth response 1 in hypoxic macrophages, as examples. RAGEcontains an unusual c-turn that mediates the DIAPH1-RAGE interaction andis required for RAGE dependent signaling (Shekhtman et al, J. Bio.Chem., 2012, 287(7) 5133-5142).

RAGE-ligand interactions evoke central changes in cellular propertiesincluding stimulation of cellular migration and proliferation andleading to such pathological conditions as diabetes and itscomplications, Alzheimer's disease, inflammation and cancers. RAGE alsoplays a pivotal role in the atherosclerotic process (Schmidt, et al.(1999) Circ Res 84, 489-497). Thus, inhibition of the RAGE activity isdesirable for treatment of these conditions.

US application publication, US2012/0088778 discloses azole derivativesas modulators of the interaction of RAGE and its ligands or RAGEactivity. The azole compounds are reported to be useful for treatment ofdiseases including acute and chronic inflammation, the development ofdiabetic late complications, and others.

US application publication, US2010/0254983 discloses methods fortreating obesity using antagonists of binding of RAGE ligands to RAGE.

US application publication, US2010/0119512 discloses carboxamidederivatives as modulators of the interaction of RAGE and its ligands orRAGE activity.

U.S. Pat. No. 7,361,678 discloses composition of 3,5-diphenyl-imidazolederivatives as modulators of the interaction of RAGE and its ligands orRAGE activity.

International application publication, WO2007/089616, discloses tertiaryamides as modulators of the interaction of RAGE and its ligands or RAGEactivity.

US application publication, US2010/0249038, discloses novel peptides asantagonists of RAGE.

Many or most of the ligands disclosed in the above applications bind tothe extracellular domain of RAGE.

In view of the above, a need exists for therapeutic agents, andcorresponding pharmaceutical compositions and related methods oftreatment that address conditions causally related to RAGE activity, andit is toward the fulfillment and satisfaction of that need, that thepresent invention is directed.

SUMMARY OF THE INVENTION

The present invention provides quinoline compounds capable of modulatingthe receptor for advanced glycation end products (RAGE) activity.

Specifically, the invention provides quinoline compounds capable ofmodulating the interaction of RAGE and its ligands, and uses of suchcompounds to treat diseases or conditions related to RAGE activity.

More specifically, the invention provides quinoline compounds capable ofmodulating the interaction of RAGE and its ligands binding to theintracellular domain of the RAGE, and uses of such compounds to treatdiseases or conditions related to RAGE activity.

In one aspect, the present invention provides a method for preventing,treating or ameliorating in a mammal a disease or condition that iscausally related to RAGE activity in vivo, which comprises administeringto the mammal an effective disease-treating or condition-treating amountof a compound according to formula C-I:

wherein

Cy is substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl;

L is a single bond, C₁-C₄ alkylenyl, —C(O)—, —S—, —S(O)—, or —S(O)₂—;

R¹ is substituted or unsubstituted C₁-C₆ alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, —OR², or—NR²R³;

each R² and R³ is independently H, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R² and R³ are joined togetherto form a substituted or unsubstituted heterocycle;

each R^(4a) is independently selected from OH, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted acyl, substituted or unsubstituted acylamino, substitutedor unsubstituted alkylamino, substituted or unsubstituted alkythio,substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkylarylamino, substituted or unsubstituted amino,substituted or unsubstituted arylalkyl, sulfo, substituted sulfo,substituted sulfonyl, substituted sulfinyl, substituted sulfanyl,substituted or unsubstituted aminosulfonyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido,substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted dialkylamino, halo,nitro, and thiol; and

R^(4b) is selected from H, OH, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstituted acyl,substituted or unsubstituted acylamino, substituted or unsubstitutedalkylamino, substituted or unsubstituted alkythio, substituted orunsubstituted alkoxycarbonyl, substituted or unsubstitutedalkylarylamino, substituted or unsubstituted amino, substituted orunsubstituted arylalkyl, sulfo, substituted sulfo, substituted sulfonyl,substituted sulfinyl, substituted sulfanyl, substituted or unsubstitutedaminosulfonyl, substituted or unsubstituted alkylsulfonyl, substitutedor unsubstituted arylsulfonyl, azido, substituted or unsubstitutedcarbamoyl, carboxyl, cyano, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted dialkylamino, halo, nitro, and thiol;

the subscript n is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt, N-oxide, solvate or prodrugthereof; and stereoisomers, isotopic variants and tautomers thereof;

provided that the compound is other than

In a further aspect, the present invention provides compounds accordingto formula C-I.

In one particular embodiment, with respect to the compound of formulaC-I, the compound is according to formula C-IIa, C-IIb, C-IIc, C-IId, orC-IIe:

wherein Cy, R¹, R^(4a), R^(4b), and n are as described herein.

In a further aspect, the present invention provides compounds accordingto formula C-I:

wherein

Cy is

R¹ is —OR², or —NR²R³;

each R² and R³ is independently H, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R² and R³ are joined togetherto form a substituted or unsubstituted heterocycle;

each R^(4a) is independently selected from OH, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted acyl, substituted or unsubstituted acylamino, substitutedor unsubstituted alkylamino, substituted or unsubstituted alkythio,substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkylarylamino, substituted or unsubstituted amino,substituted or unsubstituted arylalkyl, sulfo, substituted sulfo,substituted sulfonyl, substituted sulfinyl, substituted sulfanyl,substituted or unsubstituted aminosulfonyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido,substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted dialkylamino, halo,nitro, and thiol; and

R^(4b) is selected from H, OH, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstituted acyl,substituted or unsubstituted acylamino, substituted or unsubstitutedalkylamino, substituted or unsubstituted alkythio, substituted orunsubstituted alkoxycarbonyl, substituted or unsubstitutedalkylarylamino, substituted or unsubstituted amino, substituted orunsubstituted arylalkyl, sulfo, substituted sulfo, substituted sulfonyl,substituted sulfinyl, substituted sulfanyl, substituted or unsubstitutedaminosulfonyl, substituted or unsubstituted alkylsulfonyl, substitutedor unsubstituted arylsulfonyl, azido, substituted or unsubstitutedcarbamoyl, carboxyl, cyano, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted dialkylamino, halo, nitro, and thiol;

the subscript n is 0, 1, 2, 3, or 4;

each R⁵ is independently selected from OH, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedacyl, substituted or unsubstituted acylamino, substituted orunsubstituted alkylamino, substituted or unsubstituted alkythio,substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkylarylamino, substituted or unsubstituted amino,substituted or unsubstituted arylalkyl, sulfo, substituted sulfo,substituted sulfonyl, substituted sulfinyl, substituted sulfanyl,substituted or unsubstituted aminosulfonyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido,substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted dialkylamino, halo,nitro, and thiol;

R⁶ is substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl; and

-   -   a) L is a single bond, —CH₂—, —C(Me)H—, or —CH₂—CH₂—; X is CH,        Y′ is C—NH—C(O)—R⁶; and m is 0, 1, 2, 3, or 4;    -   b) L is —C(O)—; Y′ is C—NH—C(O)—R⁶; and m is 1, 2, 3, or 4;    -   c) L is a single bond, —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or —C(O)—;        X is N, Y′ is C—NH—C(O)—R⁶; and m is 0, 1, 2, 3, or 4;    -   d) L is —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or —C(O)—; X is N, Y′ is        CH; and m is 0, 1, 2, 3, or 4;    -   e) L is a single bond, or —C(O)—; X is N, Y′ is CH; and m is 1,        2, 3, or 4;    -   f) L is —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or —C(O)—; X is CH, Y′ is        N; and m is 0, 1, 2, 3, or 4;    -   g) L is a single bond, or —C(O)—; X is CH, Y′ is N; and m is 1,        2, 3, or 4;    -   h) L is —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or —C(O)—; Cy is

-   -   and m is 0, 1, 2, 3, or 4;    -   j) L is a single bond, or —C(O)—; Cy is

-   -   and m is 1, 2, 3, or 4; or    -   k) L is —S(O)— or —S(O)₂—; and m is 0, 1, 2, 3, or 4;    -   or a pharmaceutically acceptable salt, N-oxide, solvate or        prodrug thereof; and stereoisomers, isotopic variants and        tautomers thereof.

For the avoidance of any doubt, when Y′ is C—NH—C(O)R⁶; Cy is

In one particular embodiment, R is —OR². In another particularembodiment, R¹ is —NR²R³.

In one particular embodiment, L is a single bond, —CH₂—, —C(Me)H—, or—CH₂—CH₂—; X is CH, Y′ is C—NH—C(O)—R⁶; and m is 0, 1, 2, 3, or 4.

In another particular embodiment, L is —C(O)—; Y′ is C—NH—C(O)—R⁶; and mis 1, 2, 3, or 4.

In another particular embodiment, L is a single bond, —CH₂—, —C(Me)H—,or —CH₂—CH₂—, or —C(O)—; X is N, Y′ is C—NH—C(O)—R⁶; and m is 0, 1, 2,3, or 4.

In another particular embodiment, L is —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or—C(O)—; X is N, Y′ is CH; and m is 0, 1, 2, 3, or 4.

In another particular embodiment, L is a single bond, or —C(O)—; X is N,Y′ is CH; and m is 1, 2, 3, or 4.

In another particular embodiment, L is —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or—C(O)—; X is CH, Y′ is N; and m is 0, 1, 2, 3, or 4.

In another particular embodiment, L is a single bond, or —C(O)—; X isCH, Y′ is N; and m is 1, 2, 3, or 4.

In another particular embodiment, L is —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or—C(O)—; Cy is

and m is 0, 1, 2, 3, or 4.

In another particular embodiment, L is a single bond, or —C(O)—; Cy is

and m is 1, 2, 3, or 4.

In another particular embodiment, L is —S(O)— or —S(O)₂—; and m is 0, 1,2, 3, or 4.

In a further aspect, the present invention provides pharmaceuticalcompositions comprising amide compounds of the invention, and apharmaceutical carrier, excipient or diluent. In this aspect of theinvention, the pharmaceutical composition can comprise one or more ofthe compounds described herein. Moreover, the compounds of the presentinvention useful in the pharmaceutical compositions and treatmentmethods disclosed herein are all pharmaceutically acceptable as preparedand used.

In a further aspect, this invention provides a method of treating amammal susceptible to or afflicted with a condition from among thoselisted herein, and particularly, such condition as may be associatedwith RAGE activity. Such conditions include, without limitation,diabetes and its complications, impaired wound healing, peripheralvascular disease and associated complications, obesity, Alzheimer'sdisease, cancers, arthritis, nephropathy, acute and chronicinflammation, retinopathy, atherosclerosis, cardiovascular disease,erectile dysfunction, tumor invasion and metastases, neuropathy, cardio-and cerebrovascular ischemia/reperfusion injury, heart attack, stroke,myocardial infarction, ischemic cardiomyopathy, renal ischemia, sepsis,pneumonia, infection, liver injury, liver damage, Amyotrophic lateralsclerosis, neuropathy infection, allergy, asthma, organ damage frompollutants, amyloidoses asthma, pollution-associated tissue damage, skindisorders, colitis, skin aging, lupus, and others.

Also encompassed herein is a method for inhibiting RAGE activity in asubject (e.g., a mammal) in need thereof, the method comprisingadministering to the subject an effective RAGE-inhibiting amount of acompound as described herein so as to reduce/inhibit RAGE activity inthe subject. Such compounds may be a compound according to formula C-Ias described herein,

provided that the compound is other than

In a particular embodiment, with respect to the compound of formula C-I,the compound is according to formula C-IVa or C-IVb as described herein.

Other objects and advantages will become apparent to those skilled inthe art from a consideration of the ensuing detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a flow chart for secondary screening using NMRspectroscopy. This procedure was used to discriminate between compoundsthat bind to the C-terminal domain of RAGE, CT-RAGE, and compounds thatbind to the FH1 domain of Dia-1.

FIG. 2 depicts effects of compounds on RAGE ligand-stimulatedinflammatory gene expression in primary murine aortic endothelial cells.Inflammatory gene expression was assessed after incubation of primarymurine aortic endothelial cells with the indicated RAGE inhibitorcompounds or the parent molecule (“C12”) quinolone from the Chem-Bridgelibrary. Murine aortic endothelial cells were subjected to 1.5 hincubation with the indicated compounds (1 μM) followed by stimulationwith CML-AGE (10 μg/ml) for 6 h. Cells were then harvested and geneexpression of the inflammatory markers 116 (left) and TNFα (right)normalized to β-actin was performed by quantitative real time PCR.Assays were performed in triplicate and results are representative ofthree independent experiments. Error bars represent SEM. * indicatesp<0.05 comparing CML-AGE vs. CML-AGE and compound treatment # indicatesp<0.001 comparing CML-AGE vs. SFM vehicle (SFM). Note that SFM is thevehicle into which the RAGE ligand, CML-AGE, is added for testing theeffect of RAGE ligand.

FIG. 3 depicts effects of compounds on RAGE ligand-stimulatedinflammatory gene expression in human THP-1 cells. Inflammatory geneexpression was assessed after incubation of human THP 1 macrophage-likecells with the indicated RAGE inhibitor compounds or the parent molecule(“C12”) quinolone from the Chem-Bridge library. Human THP1 cells weresubjected to 1.5 h incubation with the indicated compounds (1 μM)followed by stimulation with CML-AGE (10 μg/ml) for 6 h. Cells were thenharvested and gene expression of the inflammatory markers IL6 (left) andTNFα (right) and normalized to β-actin was performed by quantitativereal time PCR. Assays were performed in triplicate and results arerepresentative of three independent experiments. Error bars representSEM. * indicates p<0.05 comparing CML-AGE vs. CML-AGE and compoundtreatment # indicates p<0.001 comparing CML-AGE vs. SFM vehicle (SFM).Note that SFM is the vehicle into which the RAGE ligand, CML-AGE, isadded for testing the effect of RAGE ligand.

FIG. 4 depicts effects of compounds on RAGE ligand-stimulated migrationof murine aortic smooth muscle cells (SMCs). Migration of SMCs afterincubation with the indicated RAGE inhibitor compounds or the parentmolecule (“C12”) quinolone from the Chem-Bridge library was assessed.SMCs were grown to confluence and serum-starved overnight. The followingmorning, serum free media was removed and compounds were added (1 μM).Immediately following the addition of compounds, the monolayer waswounded using a p200 pipette tip and allowed to incubate for 1.5 h.Following this incubation, compounds were removed and fresh mediacontaining RAGE ligand, CML-AGE (10 μg/ml), was added for 7 h. Allimages were measured at TO and T7 h and an area ingrowth of effectivemigrating cells was calculated. Each compound was tested in threeindependent wells and each well was photographed in 3 separate locationsfor a total of 9 images used in assessing area ingrowth. Error barsrepresent SEM. * indicates p<0.05 comparing CML-AGE vs. CML-AGE andcompound treatment and # indicates p<0.001 comparing CML-AGE vs. serumfree medium (SFM) vehicle. Note that SFM is the vehicle into which theRAGE ligand, CML-AGE, is added for testing the effect of RAGE ligand.

FIGS. 5a and 5b depict SMC migration assay curves for compounds 229 and247, respectively.

FIG. 6 depicts delayed type hypersensitivity (DTH) assay data forcompounds 203, 208, 214, 226 and 229.

DETAILED DESCRIPTION OF THE INVENTION

In that RAGE and its ligands have been positioned at the center ofchronic inflammation and it is, moreover, understood that chronicinflammation contributes significantly to the pathogenesis of diversedisorders, the compounds described herein are envisioned as useful forthe treatment of diseases wherein inflammation plays a pathological roleand RAGE contributes thereto. Such diseases and disorders includeinflammatory bowel disease, delayed-type hypersensitivity,atherosclerosis, the complications of diabetes (including neuropathy andatherosclerosis), asthma, myocardial ischemia, atherosclerosis, aneurysmformation, doxorubicin toxicity, acetaminophen toxicity,neurodegeneration, hyperlipidemia, preeclampsia, rheumatoid arthritis,pulmonary fibrosis, and Alzheimer's Disease. See, for example, Hofmannet al. (1999, Cell 97:889-901); Akirav et al. (2014, PLoS One9:e95678);Johnson et al. (2014, EJNMMI Res 4:26); Tekabe et al. (2014, Int J MolImaging 2014:695391); Song et al. (2014, Diabetes 63:1948-1965); Ullahet al. (2014, J Allergy Clin Immunol 134:440-450); Juranek et al. (2013,Brain Behav 3:701-709); Daffu et al. (2013, Int J Mol Sci14:19891-19910); Manigrasso et al. (2014, Trends Endocrinol Metab25:15-22); Tekabe et al. (2013, EJNMMi Res 3:37); Rai et al. (2012, JExp Med 209:2339-2350); Ramasamy et al. (2012, Vascular Pharmacol 57:160-167); and Arumugam et al. (2012, Clin Canc Res 18:4356-4364); theentire content of each of which is incorporated herein by reference.

Further to the above, identification of inhibitors of the interaction ofthe RAGE cytoplasmic domain with the FH1 domain of DIAPH1 holds greatpromise for the suppression of RAGE signal transduction. Extensiveexperimental evidence affirms that RAGE ligands mediate their pathogeniceffects via RAGE through the induction of intracellular signalingpathways. Hence, inhibitors that block RAGE-DIAPH1 interaction, clearlyshown to block intracellular signaling and inflammatory/cell stimulatorygene expression changes, are envisioned as therapeutic agents capable ofinhibiting the effects of RAGE ligands in chronic diseases in which theligands of RAGE accumulate. The small molecule inhibitors describedherein are, therefore, set forth as novel therapeutic agents for thetreatment of RAGE-associated diseases.

Definitions

When describing the compounds, pharmaceutical compositions containingsuch compounds and methods of using such compounds and compositions, thefollowing terms have the following meanings unless otherwise indicated.It should also be understood that any of the moieties defined forthbelow may be substituted with a variety of substituents, and that therespective definitions are intended to include such substituted moietieswithin their scope. It should be further understood that the terms“groups” and “radicals” can be considered interchangeable when usedherein.

“Acyl” refers to a radical —C(O)R²⁰, where R²⁰ is hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl,heteroarylalkyl as defined herein. Representative examples include, butare not limited to, formyl, acetyl, cyclohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like.

“Acylamino” refers to a radical —NR²¹C(O)R²², where R²¹ is hydrogen,alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl,heteroaryl, heteroarylalkyl and R²² is hydrogen, alkyl, alkoxy,cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroarylor heteroarylalkyl, as defined herein. Representative examples include,but are not limited to, formylamino, acetylamino,cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino,benzylcarbonylamino and the like.

“Acyloxy” refers to the group —OC(O)R²³ where R²³ is hydrogen, alkyl,aryl or cycloalkyl.

“Substituted alkenyl” includes those groups recited in the definition of“substituted” herein, and particularly refers to an alkenyl group having1 or more substituents, for instance from 1 to 5 substituents, andparticularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Alkoxy” refers to the group —OR²⁴ where R²⁴ is alkyl. Particular alkoxygroups include, by way of example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy,1,2-dimethylbutoxy, and the like.

“Substituted alkoxy” includes those groups recited in the definition of“substituted” herein, and particularly refers to an alkoxy group having1 or more substituents, for instance from 1 to 5 substituents, andparticularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,heteroaryl, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy,thioaryloxy, thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— andaryl-S(O)₂—.

“Alkoxycarbonylamino” refers to the group —NR²⁵C(O)OR²⁶, where R²⁵ ishydrogen, alkyl, aryl or cycloalkyl, and R²⁶ is alkyl or cycloalkyl.

“Alkyl” refers to monovalent saturated alkane radical groupsparticularly having up to about 11 carbon atoms, more particularly as alower alkyl, from 1 to 8 carbon atoms and still more particularly, from1 to 6 carbon atoms. The hydrocarbon chain may be eitherstraight-chained or branched. This term is exemplified by groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl,n-hexyl, n-octyl, tert-octyl and the like. The term “lower alkyl” refersto alkyl groups having 1 to 6 carbon atoms. The term “alkyl” alsoincludes “cycloalkyl” as defined below.

“Substituted alkyl” includes those groups recited in the definition of“substituted” herein, and particularly refers to an alkyl group having 1or more substituents, for instance from 1 to 5 substituents, andparticularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, heteroaryl, keto, nitro, thioalkoxy, substituted thioalkoxy,thioaryloxy, thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂—, andaryl-S(O)₂—.

“Alkylene” refers to divalent saturated alkene radical groups having 1to 11 carbon atoms and more particularly 1 to 6 carbon atoms which canbe straight-chained or branched. This term is exemplified by groups suchas methylene (—CH₂—), ethylene (—CH₂CH₂—), the propylene isomers (e.g.,—CH₂CH₂CH₂— and —CH(CH₃)CH₂—) and the like.

“Substituted alkylene” includes those groups recited in the definitionof “substituted” herein, and particularly refers to an alkylene grouphaving 1 or more substituents, for instance from 1 to 5 substituents,and particularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, amino-carbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, halogen, hydroxyl, keto, nitro, thioalkoxy,substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)—,aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Alkenyl” refers to monovalent olefinically unsaturated hydrocarbylgroups preferably having 2 to 11 carbon atoms, particularly, from 2 to 8carbon atoms, and more particularly, from 2 to 6 carbon atoms, which canbe straight-chained or branched and having at least 1 and particularlyfrom 1 to 2 sites of olefinic unsaturation. Particular alkenyl groupsinclude ethenyl (—CH═CH₂), n-propenyl (—CH₂CH═CH₂), isopropenyl(—C(CH₃)═CH₂), vinyl and substituted vinyl, and the like.

“Alkenylene” refers to divalent olefinically unsaturated hydrocarbylgroups particularly having up to about 11 carbon atoms and moreparticularly 2 to 6 carbon atoms which can be straight-chained orbranched and having at least 1 and particularly from 1 to 2 sites ofolefinic unsaturation. This term is exemplified by groups such asethenylene (—CH═CH—), the propenylene isomers (e.g., —CH═CHCH₂— and—C(CH₃)═CH— and —CH═C(CH₃)—) and the like.

“Alkynyl” refers to acetylenically or alkynically unsaturatedhydrocarbyl groups particularly having 2 to 11 carbon atoms, and moreparticularly 2 to 6 carbon atoms which can be straight-chained orbranched and having at least 1 and particularly from 1 to 2 sites ofalkynyl unsaturation. Particular non-limiting examples of alkynyl groupsinclude acetylenic, ethynyl (—C—CH), propargyl (—CH₂C≡CH), and the like.

“Substituted alkynyl” includes those groups recited in the definition of“substituted” herein, and particularly refers to an alkynyl group having1 or more substituents, for instance from 1 to 5 substituents, andparticularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Alkanoyl” or “acyl” as used herein refers to the group R²⁷—C(O)—, whereR²⁷ is hydrogen or alkyl as defined above.

“Aryl” refers to a monovalent aromatic hydrocarbon group derived by theremoval of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Typical aryl groups include, but are not limitedto, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene and the like. Particularly, anaryl group comprises from 6 to 14 carbon atoms.

“Substituted Aryl” includes those groups recited in the definition of“substituted” herein, and particularly refers to an aryl group that mayoptionally be substituted with 1 or more substituents, for instance from1 to 5 substituents, particularly 1 to 3 substituents, selected from thegroup consisting of acyl, acylamino, acyloxy, alkenyl, substitutedalkenyl, alkoxy, substituted alkoxy, alkoxycarbonyl, alkyl, substitutedalkyl, alkynyl, substituted alkynyl, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Fused Aryl” refers to an aryl having two of its ring carbon in commonwith a second aryl ring or with an aliphatic ring.

“Alkaryl” refers to an aryl group, as defined above, substituted withone or more alkyl groups, as defined above.

“Aralkyl” or “arylalkyl” refers to an alkyl group, as defined above,substituted with one or more aryl groups, as defined above.

“Aryloxy” refers to —O-aryl groups wherein “aryl” is as defined above.

“Alkylamino” refers to the group alkyl-NR²⁸R²⁹, wherein each of R²⁸ andR²⁹ are independently selected from hydrogen and alkyl.

“Arylamino” refers to the group aryl-NR³⁰R³¹, wherein each of R³⁰ andR³¹ are independently selected from hydrogen, aryl and heteroaryl.

“Alkoxyamino” refers to a radical —N(H)OR³² where R³² represents analkyl or cycloalkyl group as defined herein.

“Alkoxycarbonyl” refers to a radical —C(O)-alkoxy where alkoxy is asdefined herein.

“Alkylarylamino” refers to a radical —NR³³R³⁴ where R³³ represents analkyl or cycloalkyl group and R³⁴ is an aryl as defined herein.

“Alkylsulfonyl” refers to a radical —S(O)₂R³⁵ where R³⁵ is an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl,butylsulfonyl and the like.

“Alkylsulfinyl” refers to a radical —S(O)R³⁵ where R³⁵ is an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl,butylsulfinyl and the like.

“Alkylthio” refers to a radical —SR³⁵ where R³⁵ is an alkyl orcycloalkyl group as defined herein that may be optionally substituted asdefined herein. Representative examples include, but are not limited to,methylthio, ethylthio, propylthio, butylthio, and the like.

“Amino” refers to the radical —NH₂.

“Substituted amino” includes those groups recited in the definition of“substituted” herein, and particularly refers to the group —N(R³⁶)₂where each R³⁶ is independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl,and where both R groups are joined to form an alkylene group. When bothR groups are hydrogen, —N(R³⁶)₂ is an amino group.

“Aminocarbonyl” refers to the group —C(O)NR³⁷R³⁷ where each R³⁷ isindependently hydrogen, alkyl, aryl and cycloalkyl, or where the R³⁷groups are joined to form an alkylene group.

“Aminocarbonylamino” refers to the group —NR³⁸C(O)NR³⁸R³⁸ where each R³⁸is independently hydrogen, alkyl, aryl or cycloalkyl, or where two Rgroups are joined to form an alkylene group.

“Aminocarbonyloxy” refers to the group —OC(O)NR³⁹R³⁹ where each R³⁹ isindependently hydrogen, alkyl, aryl or cycloalky, or where the R groupsare joined to form an alkylene group.

“Arylalkyloxy” refers to an —O-arylalkyl radical where arylalkyl is asdefined herein.

“Arylamino” means a radical —NHR⁴⁰ where R⁴⁰ represents an aryl group asdefined herein.

“Aryloxycarbonyl” refers to a radical —C(O)—O-aryl where aryl is asdefined herein.

“Arylsulfonyl” refers to a radical —S(O)₂R⁴¹ where R⁴¹ is an aryl orheteroaryl group as defined herein.

“Azido” refers to the radical —N₃.

“Bicycloaryl” refers to a monovalent aromatic hydrocarbon group derivedby the removal of one hydrogen atom from a single carbon atom of aparent bicycloaromatic ring system. Typical bicycloaryl groups include,but are not limited to, groups derived from indane, indene, naphthalene,tetrahydronaphthalene, and the like. Particularly, an aryl groupcomprises from 8 to 11 carbon atoms.

“Bicycloheteroaryl” refers to a monovalent bicycloheteroaromatic groupderived by the removal of one hydrogen atom from a single atom of aparent bicycloheteroaromatic ring system. Typical bicycloheteroarylgroups include, but are not limited to, groups derived from benzofuran,benzimidazole, benzindazole, benzdioxane, chromene, chromane, cinnoline,phthalazine, indole, indoline, indolizine, isobenzofuran, isochromene,isoindole, isoindoline, isoquinoline, benzothiazole, benzoxazole,naphthyridine, benzoxadiazole, pteridine, purine, benzopyran,benzpyrazine, pyridopyrimidine, quinazoline, quinoline, quinolizine,quinoxaline, benzomorphan, tetrahydroisoquinoline, tetrahydroquinoline,and the like. Preferably, the bicycloheteroaryl group is between 9-11membered bicycloheteroaryl, with 5-10 membered heteroaryl beingparticularly preferred. Particular bicycloheteroaryl groups are thosederived from benzothiophene, benzofuran, benzothiazole, indole,quinoline, isoquinoline, benzimidazole, benzoxazole and benzdioxane.

“Carbamoyl” refers to the radical —C(O)N(R⁴²)₂ where each R⁴² group isindependently hydrogen, alkyl, cycloalkyl or aryl, as defined herein,which may be optionally substituted as defined herein.

“Carboxy” refers to the radical —C(O)OH.

“Carboxyamino” refers to the radical —N(H)C(O)OH.

“Cycloalkyl” refers to cyclic hydrocarbyl groups having from 3 to about10 carbon atoms and having a single cyclic ring or multiple condensedrings, including fused and bridged ring systems, which optionally can besubstituted with from 1 to 3 alkyl groups. Such cycloalkyl groupsinclude, by way of example, single ring structures such as cyclopropyl,cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl,2-methylcyclopentyl, 2-methylcyclooctyl, and the like, and multiple ringstructures such as adamantanyl, and the like.

“Substituted cycloalkyl” includes those groups recited in the definitionof “substituted” herein, and particularly refers to a cycloalkyl grouphaving 1 or more substituents, for instance from 1 to 5 substituents,and particularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Cycloalkoxy” refers to the group —OR⁴³ where R⁴³ is cycloalkyl. Suchcycloalkoxy groups include, by way of example, cyclopentoxy, cyclohexoxyand the like.

“Cycloalkenyl” refers to cyclic hydrocarbyl groups having from 3 to 10carbon atoms and having a single cyclic ring or multiple condensedrings, including fused and bridged ring systems and having at least oneand particularly from 1 to 2 sites of olefinic unsaturation. Suchcycloalkenyl groups include, by way of example, single ring structuressuch as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.

“Substituted cycloalkenyl” includes those groups recited in thedefinition of “substituted” herein, and particularly refers to acycloalkenyl group having 1 or more substituents, for instance from 1 to5 substituents, and particularly from 1 to 3 substituents, selected fromthe group consisting of acyl, acylamino, acyloxy, alkoxy, substitutedalkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Fused Cycloalkenyl” refers to a cycloalkenyl having two of its ringcarbon atoms in common with a second aliphatic or aromatic ring andhaving its olefinic unsaturation located to impart aromaticity to thecycloalkenyl ring.

“Cyanato” refers to the radical —OCN.

“Cyano” refers to the radical —CN.

“Dialkylamino” means a radical —NR⁴⁴R⁴⁵ where R⁴⁴ and R⁴⁵ independentlyrepresent an alkyl, substituted alkyl, aryl, substituted aryl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, heteroaryl, or substituted heteroaryl group as definedherein.

“Ethenyl” refers to substituted or unsubstituted —(C═C)—.

“Ethylene” refers to substituted or unsubstituted —(C—C)—.

“Ethynyl” refers to —(C≡C)—.

“Halo” or “halogen” refers to fluoro, chloro, bromo and iodo. Preferredhalo groups are either fluoro or chloro.

“Hydroxy” refers to the radical —OH.

“Nitro” refers to the radical —NO₂.

“Substituted” refers to a group in which one or more hydrogen atoms areeach independently replaced with the same or different substituent(s).Typical substituents include, but are not limited to, —X, —R⁴⁶, —O⁻, ═O,—OR⁴⁶, —SR⁴⁶, —S⁻, ═S, —NR⁴⁶R⁴⁷, ═NR⁴⁶, —CX₃, —CF₃, —CN, —OCN, —SCN,—NO, —NO₂, ═N₂, —N₃, —S(O)₂O⁻, —S(O)₂OH, —S(O)_(2R46), —OS(O₂)O⁻,—OS(O)₂R⁴⁶, —P(O)(O⁻)₂, —P(O)(OR⁴⁶)(O⁻), —OP(O)(OR⁴⁶)(OR⁴⁷), —C(O)R⁴⁶,—C(S)R⁴⁶, —C(O)OR⁴⁶, —C(O)NR⁴⁶R⁴⁷, —C(O)O⁻, —C(S)OR⁴⁶,—NR⁴⁸C(O)NR⁴⁶R⁴⁷—NR⁴⁸C(S)NR⁴⁶R⁴⁷, —NR⁴⁹C(NR⁴⁸)NR⁴⁶R⁴⁷ and—C(NR⁴⁸)NR⁴⁶R⁴⁷, where each X is independently a halogen; each R⁴⁶, R⁴⁷,R⁴⁸ and R⁴⁹ are independently hydrogen, alkyl, substituted alkyl, aryl,substituted alkyl, arylalkyl, substituted alkyl, cycloalkyl, substitutedalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl, substituted heteroarylalkyl, —NR⁵⁰R⁵¹, —C(O)R⁵⁰ or—S(O)₂R⁵⁰ or optionally R⁵⁰ and R⁵¹ together with the atom to which theyare both attached form a cycloheteroalkyl or substitutedcycloheteroalkyl ring; and R⁵⁰ and R⁵¹ are independently hydrogen,alkyl, substituted alkyl, aryl, substituted alkyl, arylalkyl,substituted alkyl, cycloalkyl, substituted alkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl or substitutedheteroarylalkyl.

Examples of representative substituted aryls include the following

In these formulae one of R⁵² and R⁵³ may be hydrogen and at least one ofR⁵² and R⁵³ is each independently selected from alkyl, alkenyl, alkynyl,cycloheteroalkyl, alkanoyl, alkoxy, aryloxy, heteroaryloxy, alkylamino,arylamino, heteroarylamino, NR⁵⁴COR⁵⁵, NR⁵⁴SOR⁵⁵, NR⁵⁴SO₂R⁵⁷, COOalkyl,COOaryl, CONR⁵⁴R⁵⁵, CONR⁵⁴OR⁵⁵, NR⁵⁴R⁵⁵, SO₂NR⁵⁴R⁵⁵, S-alkyl, S-alkyl,SOalkyl, SO₂alkyl, Saryl, SOaryl, SO₂aryl; or R⁵² and R⁵³ may be joinedto form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms,optionally containing one or more heteroatoms selected from the group N,O or S. R⁵⁴, R⁵⁵, and R⁵⁶ are independently hydrogen, alkyl, alkenyl,alkynyl, perfluoroalkyl, cycloalkyl, cycloheteroalkyl, aryl, substitutedaryl, heteroaryl, substituted or hetero alkyl or the like.

“Hetero” when used to describe a compound or a group present on acompound means that one or more carbon atoms in the compound or grouphave been replaced by a nitrogen, oxygen, or sulfur heteroatom. Heteromay be applied to any of the hydrocarbyl groups described above such asalkyl, e.g. heteroalkyl, cycloalkyl, e.g. cycloheteroalkyl, aryl, e.g.heteroaryl, cycloalkenyl, cycloheteroalkenyl, and the like having from 1to 5, and especially from 1 to 3 heteroatoms.

“Heteroaryl” refers to a monovalent heteroaromatic group derived by theremoval of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Typical heteroaryl groups include, but arenot limited to, groups derived from acridine, arsindole, carbazole,β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole,indole, indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, phenanthridine, phenanthroline, phenazine,phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine,pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline,quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene,triazole, xanthene, and the like. Preferably, the heteroaryl group isbetween 5-15 membered heteroaryl, with 5-10 membered heteroaryl beingparticularly preferred. Particular heteroaryl groups are those derivedfrom thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine,quinoline, imidazole, oxazole and pyrazine.

Examples of representative heteroaryls include the following:

wherein each Y is selected from carbonyl, N, NR⁵⁸, O, and S; and R⁵⁸ isindependently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,heteroaryl, heteroalkyl or the like.

As used herein, the term “cycloheteroalkyl” or “heterocycloalkyl” refersto a stable heterocyclic non-aromatic ring and fused rings containingone or more heteroatoms independently selected from N, O and S. A fusedheterocyclic ring system may include carbocyclic rings and need onlyinclude one heterocyclic ring. Examples of heterocyclic rings include,but are not limited to, piperazinyl, homopiperazinyl, piperidinyl andmorpholinyl, and are shown in the following illustrative examples:

wherein each X is selected from CR⁵⁸ ₂, NR⁵⁸, O and S; and each Y isselected from NR⁵⁸, O and S; and R⁵⁸ is independently hydrogen, alkyl,cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heteroalkyl or the like.These cycloheteroalkyl rings may be optionally substituted with one ormore groups selected from the group consisting of acyl, acylamino,acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl,alkoxycarbonylamino, amino, substituted amino, aminocarbonyl,aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl,cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto,nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—. Substitutinggroups include carbonyl or thiocarbonyl which provide, for example,lactam and urea derivatives.

Examples of representative cycloheteroalkenyls include the following:

wherein each X is selected from CR⁵⁸ ₂, NR⁵⁸, O and S; and each Y isselected from carbonyl, N, NR⁵⁸, O and S; and R⁵⁸ is independentlyhydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl,heteroalkyl or the like.

Examples of representative aryl having hetero atoms containingsubstitution include the following:

wherein each X is selected from C—R⁵⁸ ₂ NR⁵⁸, O and S; and each Y isselected from carbonyl, NR⁵⁸, O and S; and R⁵⁸ is independentlyhydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl,heteroalkyl or the like.

“Hetero substituent” refers to a halo, O, S or N atom-containingfunctionality that may be present as an R⁴ in a R⁴C group present assubstituents directly on A, B, W, Y or Z of the compounds of thisinvention or may be present as a substituent in the “substituted” aryland aliphatic groups present in the compounds.

Examples of hetero substituents include:

-   -   -halo,    -   —NO₂, —NH₂, —NHR⁵⁹, —N(R⁵⁹)₂,    -   —NRCOR, —NR⁵⁹SOR⁵⁹, —NR⁵⁹SO₂R⁵⁹, OH, CN,    -   —CO₂H,    -   —R⁵⁹—OH, —O—R⁵⁹, —COOR⁵⁹,    -   —CON(R⁵⁹)₂, —CONROR⁵⁹,    -   —SO₃H, —R⁵⁹—S, —SO₂N(R⁵⁹⁾ ²,

—S(O)R⁵⁹, —S(O)₂R⁵⁹

wherein each R⁵⁹ is independently an aryl or aliphatic, optionally withsubstitution. Among hetero substituents containing R⁵⁹ groups,preference is given to those materials having aryl and alkyl R⁵⁹ groupsas defined herein. Preferred hetero substituents are those listed above.

“Hydrogen bond donor” group refers to a group containg O—H, or N—Hfunctionality. Examples of “hydrogen bond donor” groups include —OH,—NH₂, and —NH—R^(59a) and wherein R^(59a) is alkyl, cycloalkyl, aryl, orheteroaryl.

“Dihydroxyphosphoryl” refers to the radical —PO(OH)₂.

“Substituted dihydroxyphosphoryl” includes those groups recited in thedefinition of “substituted” herein, and particularly refers to adihydroxyphosphoryl radical wherein one or both of the hydroxyl groupsare substituted. Suitable substituents are described in detail below.

“Aminohydroxyphosphoryl” refers to the radical —PO(OH)NH₂.

“Substituted aminohydroxyphosphoryl” includes those groups recited inthe definition of “substituted” herein, and particularly refers to anaminohydroxyphosphoryl wherein the amino group is substituted with oneor two substituents. Suitable substituents are described in detailbelow. In certain embodiments, the hydroxyl group can also besubstituted.

“Thioalkoxy” refers to the group —SR⁶⁰ where R⁶⁰ is alkyl.

“Substituted thioalkoxy” includes those groups recited in the definitionof “substituted” herein, and particularly refers to a thioalkoxy grouphaving 1 or more substituents, for instance from 1 to 5 substituents,and particularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Sulfanyl” refers to the radical HS—. “Substituted sulfanyl” refers to aradical such as RS— wherein R is any substituent described herein.

“Sulfonyl” refers to the divalent radical —S(O₂)—. “Substitutedsulfonyl” refers to a radical such as R⁶¹—(O₂)S— wherein R⁶¹ is anysubstituent described herein. “Aminosulfonyl” or “Sulfonamide” refers tothe radical H₂N(O₂)S—, and “substituted aminosulfonyl” “substitutedsulfonamide” refers to a radical such as R⁶² ₂N(O₂)S— wherein each R⁶²is independently any substituent described herein.

“Sulfone” refers to the group —SO₂R⁶³. In particular embodiments, R⁶³ isselected from H, lower alkyl, alkyl, aryl and heteroaryl.

“Thioaryloxy” refers to the group —SR⁶⁴ where R⁶⁴ is aryl.

“Thioketo” refers to the group ═S.

“Thiol” refers to the group —SH.

One having ordinary skill in the art of organic synthesis will recognizethat the maximum number of heteroatoms in a stable, chemically feasibleheterocyclic ring, whether it is aromatic or non aromatic, is determinedby the size of the ring, the degree of unsaturation and the valence ofthe heteroatoms. In general, a heterocyclic ring may have one to fourheteroatoms so long as the heteroaromatic ring is chemically feasibleand stable.

“Pharmaceutically acceptable” means approved by a regulatory agency ofthe Federal or a state government or listed in the U.S. Pharmacopoeia orother generally recognized pharmacopoeia for use in animals, and moreparticularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of theinvention that is pharmaceutically acceptable and that possesses thedesired pharmacological activity of the parent compound. Such saltsinclude: (1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe compound contains a basic functionality, salts of non toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like. The term“pharmaceutically acceptable cation” refers to a non toxic, acceptablecationic counter-ion of an acidic functional group. Such cations areexemplified by sodium, potassium, calcium, magnesium, ammonium,tetraalkylammonium cations, and the like.

“Pharmaceutically acceptable vehicle” or “Pharmaceutically acceptablecarrier” refer to a pharmaceutically acceptable diluent, apharmaceutically acceptable adjuvant, a pharmaceutically acceptableexcipient, or a combination of any of the foregoing with which acomposition provided by the present disclosure may be administered to apatient and which does not destroy the pharmacological activity thereofand which is non-toxic when administered in doses sufficient to providea therapeutically effective amount of the composition. In addition tothe adjuvants, excipients and diluents known to one skilled in the art,the vehicle or carrier includes nanoparticles of organic and inorganicnature.

“Preventing” or “prevention” refers to a reduction in risk of acquiringa disease or disorder (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a subject that may be exposedto or predisposed to the disease but does not yet experience or displaysymptoms of the disease).

“Prodrugs” refers to compounds, including derivatives of the compoundsof the invention, which have cleavable groups and become by solvolysisor under physiological conditions the compounds of the invention whichare pharmaceutically active in vivo. Such examples include, but are notlimited to, choline ester derivatives and the like, N-alkylmorpholineesters and the like.

“Solvate” refers to forms of the compound that are associated with asolvent, usually by a solvolysis reaction. Conventional solvents includewater, ethanol, acetic acid and the like. The compounds of the inventionmay be prepared e.g. in crystalline form and may be solvated orhydrated. Suitable solvates include pharmaceutically acceptablesolvates, such as hydrates, and further include both stoichiometricsolvates and non-stoichiometric solvates.

“Subject” includes humans. The terms “human,” “patient” and “subject”are used interchangeably herein.

“Therapeutically effective amount” means the amount of a compound that,when administered to a subject for treating a disease, is sufficient toeffect such treatment for the disease. The “therapeutically effectiveamount” can vary depending on the compound, the disease and itsseverity, and the age, weight, etc., of the subject to be treated.

“Treating” or “treatment” of any disease or disorder refers, in oneembodiment, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof). In another embodiment “treating” or “treatment”refers to ameliorating at least one physical parameter, which may not bediscernible by the subject. In yet another embodiment, “treating” or“treatment” refers to modulating the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.

As used herein, the term “operably linked” refers to a regulatorysequence capable of mediating the expression of a coding sequence andwhich is placed in a DNA molecule (e.g., an expression vector) in anappropriate position relative to the coding sequence so as to effectexpression of the coding sequence. This same definition is sometimesapplied to the arrangement of coding sequences and transcription controlelements (e.g. promoters, enhancers, and termination elements) in anexpression vector. This definition is also sometimes applied to thearrangement of nucleic acid sequences of a first and a second nucleicacid molecule wherein a hybrid nucleic acid molecule is generated.

A “vector” is a replicon, such as a plasmid, cosmid, bacmid, phage orvirus, to which another genetic sequence or element (either DNA or RNA)may be attached so as to bring about the replication of the attachedsequence or element.

An “expression vector” or “expression operon” refers to a nucleic acidsegment that may possess transcriptional and translational controlsequences, such as promoters, enhancers, translational start signals(e.g., ATG or AUG codons), polyadenylation signals, terminators, and thelike, and which facilitate the expression of a polypeptide codingsequence in a host cell or organism.

The terms “transform”, “transfect”, or “transduce”, shall refer to anymethod or means by which a nucleic acid is introduced into a cell orhost organism and may be used interchangeably to convey the samemeaning. Such methods include, but are not limited to, transfection,electroporation, microinjection, PEG-fusion and the like.

The introduced nucleic acid may or may not be integrated (covalentlylinked) into nucleic acid of the recipient cell or organism. Inbacterial, yeast, plant and mammalian cells, for example, the introducednucleic acid may be maintained as an episomal element or independentreplicon such as a plasmid. Alternatively, the introduced nucleic acidmay become integrated into the nucleic acid of the recipient cell ororganism and may be stably maintained in that cell or organism andfurther passed on or inherited to progeny cells or organisms of therecipient cell or organism. In other applications, the introducednucleic acid may exist in the recipient cell or host organism onlytransiently.

The phrase “consisting essentially of” when referring to a particularnucleotide or amino acid means a sequence having the properties of agiven SEQ ID NO:. For example, when used in reference to an amino acidsequence, the phrase includes the sequence per se and molecularmodifications that would not affect the basic and novel characteristicsof the sequence.

Other derivatives of the compounds of this invention have activity inboth their acid and acid derivative forms, but in the acid sensitiveform often offers advantages of solubility, tissue compatibility, ordelayed release in the mammalian organism (see, Bundgard, H., Design ofProdrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs includeacid derivatives well known to practitioners in the art, such as, forexample, esters prepared by reaction of the parent acid with a suitablealcohol, or amides prepared by reaction of the parent acid compound witha substituted or unsubstituted amine, or acid anhydrides, or mixedanhydrides. Simple aliphatic or aromatic esters, amides and anhydridesderived from acidic groups pendant on the compounds of this inventionare preferred prodrugs. In some cases it is desirable to prepare doubleester type prodrugs such as (acyloxy)alkyl esters or((alkoxycarbonyl)oxy)alkylesters. Preferred are the C₁ to C₈ alkyl,C₂-C₈ alkenyl, aryl, C₇-C₁₂ substituted aryl, and C₇-C₁₂ arylalkylesters of the compounds of the invention.

As used herein, the term “isotopic variant” refers to a compound thatcontains unnatural proportions of isotopes at one or more of the atomsthat constitute such compound. For example, an “isotopic variant” of acompound can contain one or more non-radioactive isotopes, such as forexample, deuterium (²H or D), carbon-13 (¹³C), nitrogen-15 (¹⁵N), or thelike. It will be understood that, in a compound where such isotopicsubstitution is made, the following atoms, where present, may vary, sothat for example, any hydrogen may be ²H/D, any carbon may be ¹³C, orany nitrogen may be ¹⁵N, and that the presence and placement of suchatoms may be determined within the skill of the art. Likewise, theinvention may include the preparation of isotopic variants withradioisotopes, in the instance for example, where the resultingcompounds may be used for drug and/or substrate tissue distributionstudies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e.¹⁴C, are particularly useful for this purpose in view of their ease ofincorporation and ready means of detection. Further, compounds may beprepared that are substituted with positron emitting isotopes, such as¹¹C, ¹⁸F, ¹⁵O and ¹³N, and would be useful in Positron EmissionTopography (PET) studies for examining substrate receptor occupancy.

All isotopic variants of the compounds provided herein, radioactive ornot, are intended to be encompassed within the scope of the invention.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers”. Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers”.

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers”. When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

“Tautomers” refer to compounds that are interchangeable forms of aparticular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of t electrons and an atom (usually H). Forexample, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. Another example oftautomerism is the aci- and nitro-forms of phenylnitromethane, that arelikewise formed by treatment with acid or base.

Tautomeric forms may be relevant to the attainment of the optimalchemical reactivity and biological activity of a compound of interest.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers andmixtures, racemic or otherwise, thereof. The methods for thedetermination of stereochemistry and the separation of stereoisomers arewell-known in the art.

The Compounds

The present invention provides quinoline compounds capable of modulatingthe receptor for advanced glycation end products (RAGE) activity.

Specifically, the invention provides quinoline compounds capable ofmodulating the interaction of RAGE and its ligands, and uses of suchcompounds to treat diseases or conditions related to RAGE activity.

More specifically, the invention provides quinoline compounds capable ofmodulating the interaction of RAGE and its ligands binding to theintracellular domain of the RAGE, and uses of such compounds to treatdiseases or conditions related to RAGE activity.

In one aspect, the present invention provides a method for preventing,treating or ameliorating in a mammal a disease or condition that iscausally related to RAGE activity in vivo, which comprises administeringto the mammal an effective disease-treating or condition-treating amountof a compound according to formula C-I:

wherein

Cy is substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl;

L is a single bond, C₁-C₄ alkylenyl, —C(O)—, —S—, —S(O)—, or —S(O)₂—;

R¹ is substituted or unsubstituted C₁-C₆ alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, —OR², or—NR²R³;

each R² and R³ is independently H, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R² and R³ are joined togetherto form a substituted or unsubstituted heterocycle;

each R^(4a) is independently selected from OH, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted acyl, substituted or unsubstituted acylamino, substitutedor unsubstituted alkylamino, substituted or unsubstituted alkythio,substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkylarylamino, substituted or unsubstituted amino,substituted or unsubstituted arylalkyl, sulfo, substituted sulfo,substituted sulfonyl, substituted sulfinyl, substituted sulfanyl,substituted or unsubstituted aminosulfonyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido,substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted dialkylamino, halo,nitro, and thiol; and

R^(4b) is selected from H, OH, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstituted acyl,substituted or unsubstituted acylamino, substituted or unsubstitutedalkylamino, substituted or unsubstituted alkythio, substituted orunsubstituted alkoxycarbonyl, substituted or unsubstitutedalkylarylamino, substituted or unsubstituted amino, substituted orunsubstituted arylalkyl, sulfo, substituted sulfo, substituted sulfonyl,substituted sulfinyl, substituted sulfanyl, substituted or unsubstitutedaminosulfonyl, substituted or unsubstituted alkylsulfonyl, substitutedor unsubstituted arylsulfonyl, azido, substituted or unsubstitutedcarbamoyl, carboxyl, cyano, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted dialkylamino, halo, nitro, and thiol;

the subscript n is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt, N-oxide, solvate or prodrugthereof; and stereoisomers, isotopic variants and tautomers thereof;

provided that the compound is other than

In one aspect, the present invention provides compounds according toformula C-I:

wherein

Cy is substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl;

L is a single bond, C₁-C₄ alkylenyl, —C(O)—, —S—, —S(O)—, or —S(O)₂—;

R¹ is substituted or unsubstituted C₁-C₆ alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, —OR², or—NR²R³;

each R² and R³ is independently H, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R² and R³ are joined togetherto form a substituted or unsubstituted heterocycle;

each R^(4a) is independently selected from OH, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted acyl, substituted or unsubstituted acylamino, substitutedor unsubstituted alkylamino, substituted or unsubstituted alkythio,substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkylarylamino, substituted or unsubstituted amino,substituted or unsubstituted arylalkyl, sulfo, substituted sulfo,substituted sulfonyl, substituted sulfinyl, substituted sulfanyl,substituted or unsubstituted aminosulfonyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido,substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted dialkylamino, halo,nitro, and thiol; and

R^(4b) is selected from H, OH, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstituted acyl,substituted or unsubstituted acylamino, substituted or unsubstitutedalkylamino, substituted or unsubstituted alkythio, substituted orunsubstituted alkoxycarbonyl, substituted or unsubstitutedalkylarylamino, substituted or unsubstituted amino, substituted orunsubstituted arylalkyl, sulfo, substituted sulfo, substituted sulfonyl,substituted sulfinyl, substituted sulfanyl, substituted or unsubstitutedaminosulfonyl, substituted or unsubstituted alkylsulfonyl, substitutedor unsubstituted arylsulfonyl, azido, substituted or unsubstitutedcarbamoyl, carboxyl, cyano, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted dialkylamino, halo, nitro, and thiol;

the subscript n is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt, N-oxide, solvate or prodrugthereof;

and stereoisomers, isotopic variants and tautomers thereof;provided that the compound is other than

In one embodiment, with respect to the compounds of formula C-I, thecompound is according to formula C-IVd, C-IVe, C-Vd, C-Ve, C-VId, C-VIe,C-VIIa-C-VIIe, C-VIIIa, C-VIIIb, C-VIIId, C-VIIIe, C-IXa, C-IXb, C-IXd,C-IXe, C-Xa, C-Xb, C-Xd, C-Xe, C-XIa, C-XIb, C-XId, C-XIe, C-XIIb,C-XIId, C-XIIe, C-XIIIa-C-XIIIe, C-XVIa, C-XVIb, C-XVId, C-XVIe, orC-XVIIa-C-XVIIe.

In one embodiment, with respect to the compounds of formula C-I, thecompound is according to formula C-XIIa, and R¹ is —OR² or —NR²R³.

In one embodiment, with respect to the compounds of formula C-I, thecompound is according to formula C-XVIc, R⁶ is Me or Et, and Y is NH.

In one embodiment, with respect to the compounds of formula C-I, thecompound is according to formula C-IId or C-IIe, and Cy is other thanunsubstituted phenyl.

In one embodiment, with respect to the compounds of formula C-I, L is asingle bond.

In one embodiment, L is substituted or unsubstituted alkylenyl.

In one embodiment, with respect to the compounds of formula C-I, L is—CH₂, —CH₂—CH₂—, or —CH₂—CH₂—CH₂—. In another embodiment, L is —CH₂—. Inanother embodiment, L is —C(alkyl)H—. In another embodiment, L is—C(Me)H—. In another embodiment, L is —C(Et)H—. In another embodiment, Lis —C(i-Pr)H—. In another embodiment, L is —C(Me)₂-. In anotherembodiment, L is —C(O)—. In another embodiment, L is —S(O)—, or —S(O)₂—.In another embodiment, L is —S—.

In one embodiment, with respect to the compounds of formula C-I, thecompound is according to formula C-IIa, C-IIb, C-IIc, C-IId, or C-IIe:

wherein Cy, R¹, R^(4a), R^(4b), and n are as described for formula C-I.

In one embodiment, Cy is substituted or unsubstituted aryl.

In another embodiment, Cy is substituted or unsubstituted phenyl ornaphthyl.

In another embodiment, Cy is substituted or unsubstituted phenyl.

In another embodiment, Cy is substituted or unsubstituted heteroaryl.

In another embodiment, Cy is substituted or unsubstituted pyridyl,pyrimidinyl, or pyrazinyl.

In another embodiment, Cy is substituted or unsubstituted 2-pyridyl,3-pyridyl, or 4-pyridyl.

In another embodiment, Cy is substituted or unsubstituted pyrrolyl,furanyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, or tetrazolyl.

In one embodiment, with respect to the compounds of formula C-I, thecompound is according to formula C-IIIa, C-IIIb, C-IIIc, C-IIId, orC-IIIe:

wherein R¹, R^(4a), R^(4b), and n are as described for formula C-I; eachX and Y′ is independently —CH—, or —N—;

each R⁵ is independently selected from OH, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedacyl, substituted or unsubstituted acylamino, substituted orunsubstituted alkylamino, substituted or unsubstituted alkythio,substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkylarylamino, substituted or unsubstituted amino,substituted or unsubstituted arylalkyl, sulfo, substituted sulfo,substituted sulfonyl, substituted sulfinyl, substituted sulfanyl,substituted or unsubstituted aminosulfonyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido,substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted dialkylamino, halo,nitro, and thiol; and the subscript m is 0, 1, 2, 3, or 4.

In one embodiment, X is N.

In another embodiment, Y′ is N.

In another embodiment, X is N and Y′ is CH.

In another embodiment, X is CH and Y′ is N.

In a further aspect, the present invention provides compounds accordingto formula C-I:

wherein Cy is

R¹ is —OR², or —NR²R³;

each R² and R³ is independently H, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl; R² and R³ are joined togetherto form a substituted or unsubstituted heterocycle;

each R^(4a) is independently selected from OH, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted acyl, substituted or unsubstituted acylamino, substitutedor unsubstituted alkylamino, substituted or unsubstituted alkythio,substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkylarylamino, substituted or unsubstituted amino,substituted or unsubstituted arylalkyl, sulfo, substituted sulfo,substituted sulfonyl, substituted sulfinyl, substituted sulfanyl,substituted or unsubstituted aminosulfonyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido,substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted dialkylamino, halo,nitro, and thiol; and

R^(4b) is selected from H, OH, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstituted acyl,substituted or unsubstituted acylamino, substituted or unsubstitutedalkylamino, substituted or unsubstituted alkythio, substituted orunsubstituted alkoxycarbonyl, substituted or unsubstitutedalkylarylamino, substituted or unsubstituted amino, substituted orunsubstituted arylalkyl, sulfo, substituted sulfo, substituted sulfonyl,substituted sulfinyl, substituted sulfanyl, substituted or unsubstitutedaminosulfonyl, substituted or unsubstituted alkylsulfonyl, substitutedor unsubstituted arylsulfonyl, azido, substituted or unsubstitutedcarbamoyl, carboxyl, cyano, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted dialkylamino, halo, nitro, and thiol;

the subscript n is 0, 1, 2, 3, or 4;

each R⁵ is independently selected from OH, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedacyl, substituted or unsubstituted acylamino, substituted orunsubstituted alkylamino, substituted or unsubstituted alkythio,substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkylarylamino, substituted or unsubstituted amino,substituted or unsubstituted arylalkyl, sulfo, substituted sulfo,substituted sulfonyl, substituted sulfinyl, substituted sulfanyl,substituted or unsubstituted aminosulfonyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido,substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted dialkylamino, halo,nitro, and thiol;

R⁶ is substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl; and

-   -   a) L is a single bond, —CH₂—, —C(Me)H—, or —CH₂—CH₂—; X is CH,        Y′ is C—NH—C(O)—R⁶; and m is 0, 1, 2, 3, or 4;    -   b) L is —C(O)—; Y′ is C—NH—C(O)—R⁶; and m is 1, 2, 3, or 4;    -   c) L is a single bond, —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or —C(O)—;        X is N, Y′ is C—NH—C(O)—R⁶; and m is 0, 1, 2, 3, or 4;    -   d) L is —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or —C(O)—; X is N, Y′ is        CH; and m is 0, 1, 2, 3, or 4;    -   e) L is a single bond, or —C(O)—; X is N, Y′ is CH; and m is 1,        2, 3, or 4;    -   f) L is —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or —C(O)—; X is CH, Y′ is        N; and m is 0, 1, 2, 3, or 4;    -   g) L is a single bond, or —C(O)—; X is CH, Y′ is N; and m is 1,        2, 3, or 4;    -   h) L is —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or —C(O)—; Cy is

-   -   and m is 0, 1, 2, 3, or 4;    -   j) L is a single bond, or —C(O)—; Cy is

-   -   and m is 1, 2, 3, or 4; or    -   k) L is —S(O)— or —S(O)₂—; and m is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt, N-oxide, solvate or prodrugthereof;

and stereoisomers, isotopic variants and tautomers thereof.

In one particular embodiment, R¹ is —OR². In another particularembodiment, R¹ is —NR²R³.

In one particular embodiment, L is a single bond, —CH₂—, —C(Me)H—, or—CH₂—CH₂—; X is CH, Y′ is C—NH—C(O)—R⁶; and m is 0, 1, 2, 3, or 4.

In another particular embodiment, L is —C(O)—; Y′ is C—NH—C(O)—R⁶; and mis 1, 2, 3, or 4.

In another particular embodiment, L is a single bond, —CH₂—, —C(Me)H—,or —CH₂—CH₂—, or —C(O)—; X is N, Y′ is C—NH—C(O)—R⁶; and m is 0, 1, 2,3, or 4.

In another particular embodiment, L is —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or—C(O)—; X is N, Y′ is CH; and m is 0, 1, 2, 3, or 4.

In another particular embodiment, L is a single bond, or —C(O)—; X is N,Y′ is CH; and m is 1, 2, 3, or 4.

In another particular embodiment, L is —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or—C(O)—; X is CH, Y′ is N; and m is 0, 1, 2, 3, or 4.

In another particular embodiment, L is a single bond, or —C(O)—; X isCH, Y′ is N; and m is 1, 2, 3, or 4.

In another particular embodiment, L is —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or—C(O)—; Cy is

and m is 0, 1, 2, 3, or 4.

In another particular embodiment, L is a single bond, or —C(O)—; Cy is

and m is 1, 2, 3, or 4.

In another particular embodiment, L is —S(O)— or —S(O)₂—; and m is 0, 1,2, 3, or 4.

In one embodiment, with respect to the compounds of formula C-I, thecompound is according to formula C-IVa, C-IVb, C-IVc, C-IVd, or C-IVe:

wherein R¹, R^(4a), R^(4b), and n are as described for formula C-I; andR⁶ is substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl.

In one embodiment, with respect to the compounds of formula C-I, thecompound is according to formula C-Va, C-Vb, C-Vc, C-Vd, or C-Ve:

wherein R¹, R^(4a), R^(4b), and n are as described for formula C-I.

In one embodiment, with respect to the compounds of formula C-I, thecompound is according to formula C-VIa, C-VIb, C-VIc, C-VId, or C-VIe:

wherein R, R^(4a), R^(4b), and n are as described for formula C-I.

In one embodiment, with respect to the compounds of formula C-I, thecompound is according to formula C-VIIa, C-VIIb, C-VIIc, C-VIId, orVIIe:

wherein R¹, R^(4a), R^(4b), and n are as in claim 1; and R⁶ issubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl.

In one embodiment, R^(4b) is halo, CN, substituted or unsubstitutedalkyl, or substituted or unsubstituted alkoxy.

In another embodiment, R^(4b) is F, Cl, CN, Me, Et, i-Pr, OMe, OEt, orCF₃.

In a particular embodiment, R^(4b) is H.

In one embodiment, with respect to the compounds of formula C-I, thecompound is according to formula C-VIIIa, C-VIIIb, C-VIIIc, C-VIIId, orC-VIIIe:

wherein R¹, R^(4a), and n are as described for formula C-I; and R⁶ issubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl.

In one embodiment, with respect to the compounds of formula C-I, thecompound is according to formula C-IXa, C-IXb, C-IXc, C-IXd, or C-IXe:

wherein R¹, R^(4a), and n are as described for formula C-I; and R⁶ issubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl.

In one embodiment, with respect to the compounds of formula C-I, thecompound is according to formula C-Xa, C-Xb, C-Xc, C-Xd, or C-Xe:

wherein R¹, R^(4a), and n are as described for formula C-I.

In one embodiment, with respect to the compounds of formula C-I, thecompound is according to formula C-XIa, C-XIa, C-XIb, C-XIc, C-XId, orC-XIe:

wherein R¹, R^(4a), and n are as described for formula C-I.

In one embodiment, n is 1, 2, 3, or 4.

In another embodiment, n is 1 or 2.

In another embodiment, n is 1.

In another embodiment, each R^(4a) is independently selected from halo,CN, substituted or unsubstituted alkyl, and substituted or unsubstitutedalkoxy.

In another embodiment, each R^(4a) is independently selected from F, Cl,CN, Me, Et, i-Pr, OMe, OEt, and CF₃. In a particular embodiment, R^(4a)is CN, OMe, or F. In one embodiment, R^(4a) is at 6-position. In aparticular embodiment, R^(4a) is at 7-position.

In a particular embodiment, n is 0.

In one embodiment, with respect to the compounds of formula C-I, thecompound is according to formula C-XIIa, C-XIIb, C-XIIc, C-XIId, orC-XIIe:

wherein R¹ is as described for formula C-I; and R⁶ is substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

In one embodiment, with respect to the compounds of formula C-I, thecompound is according to formula C-XIIIa, C-XIIIb, C-XIIIc, C-XIIId, orC-XIIIe:

wherein R¹ is as described for formula C-I; and R⁶ is substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

In one embodiment, with respect to the compounds of formula C-I, thecompound is according to formula C-XIVa, C-XIVb, C-XIVc, C-XIVd, orC-XIVe:

wherein R¹ is as described for formula C-I.

In one embodiment, with respect to the compounds of formula C-I, thecompound is according to formula C-XVa, C-XVb, C-XIVc, C-XIVd, or C-XVe:

wherein R¹ is as described for formula C-I.

In one embodiment, R¹ is substituted or unsubstituted C₁-C₆ alkyl.

In another embodiment, R¹ is Me, Et, i-Pr, n-Pr, n-Bu, or t-Bu.

In another embodiment, R¹ is —OR²; and R² is H, substituted orunsubstituted C₁-C₆ alkyl, or substituted or unsubstituted cycloalkyl.

In another embodiment, R¹ is OMe, OEt, or O-i-Pr.

In another embodiment, R¹ is —NR²R³; and each R² and R³ is independentlyH, substituted or unsubstituted C₁-C₆ alkyl, or substituted orunsubstituted cycloalkyl.

In another embodiment, R¹ is —NR²R³; and each R² and R³ is independentlyH, Me, Et, i-Pr, n-Pr, n-Bu, or t-Bu.

In another embodiment, R¹ is —NR²R³; and R² is H or Me; and R³ is Me,Et, i-Pr, n-Pr, n-Bu, or t-Bu.

In another embodiment, R¹ is —NR²R³; and R² is H or Me; and R³ is Et,i-Pr, n-Pr, n-Bu, or t-Bu; each of which is substituted with hydroxyl,alkoxy, amino, alkylamino, or dialkylamino.

In a particular embodiment, R¹ is —N(Me)-CH₂—CH₂—OMe, In anotherparticular embodiment, R¹ is —N(Me)-CH₂—CH₂-Me. In another particularembodiment, R¹ is —N(Me)-CH₂—CH₂—CH₂-Me.

In another embodiment, R¹ is —NR²R³; and R² and R³ are joined togetherto form a substituted or unsubstituted heterocycle.

In another embodiment, R¹ is pyrrolidin-1-yl, piperidin-1-yl,piperizin-l-yl, or morpholin-1-yl.

In yet another aspect, the present invention provides compoundsaccording to formula C-I:

wherein Cy is

R¹ is

Y is CH₂, NH, or O;

each R^(4a) is independently selected from OH, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted acyl, substituted or unsubstituted acylamino, substitutedor unsubstituted alkylamino, substituted or unsubstituted alkythio,substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkylarylamino, substituted or unsubstituted amino,substituted or unsubstituted arylalkyl, sulfo, substituted sulfo,substituted sulfonyl, substituted sulfinyl, substituted sulfanyl,substituted or unsubstituted aminosulfonyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido,substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted dialkylamino, halo,nitro, and thiol; and

R^(4b) is selected from H, OH, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstituted acyl,substituted or unsubstituted acylamino, substituted or unsubstitutedalkylamino, substituted or unsubstituted alkythio, substituted orunsubstituted alkoxycarbonyl, substituted or unsubstitutedalkylarylamino, substituted or unsubstituted amino, substituted orunsubstituted arylalkyl, sulfo, substituted sulfo, substituted sulfonyl,substituted sulfinyl, substituted sulfanyl, substituted or unsubstitutedaminosulfonyl, substituted or unsubstituted alkylsulfonyl, substitutedor unsubstituted arylsulfonyl, azido, substituted or unsubstitutedcarbamoyl, carboxyl, cyano, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted dialkylamino, halo, nitro, and thiol;

the subscript n is 0, 1, 2, 3, or 4;

each R⁵ is independently selected from OH, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedacyl, substituted or unsubstituted acylamino, substituted orunsubstituted alkylamino, substituted or unsubstituted alkythio,substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkylarylamino, substituted or unsubstituted amino,substituted or unsubstituted arylalkyl, sulfo, substituted sulfo,substituted sulfonyl, substituted sulfinyl, substituted sulfanyl,substituted or unsubstituted aminosulfonyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido,substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted dialkylamino, halo,nitro, and thiol;

R⁶ is substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl; and

-   -   a) L is a single bond, —CH₂—, —C(Me)H—, or —CH₂—CH₂—; X is CH,        Y′ is C—NH—C(O)—R⁶; and m is 0, 1, 2, 3, or 4;    -   b) L is —C(O)—; Y′ is C—NH—C(O)—R⁶; and m is 1, 2, 3, or 4;    -   c) L is a single bond, —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or —C(O)—;        X is N, Y′ is C—NH—C(O)—R⁶; and m is 0, 1, 2, 3, or 4;    -   d) L is —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or —C(O)—; X is N, Y′ is        CH; and m is 0, 1, 2, 3, or 4;    -   e) L is a single bond, or —C(O)—; X is N, Y′ is CH; and m is 1,        2, 3, or 4;    -   f) L is —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or —C(O)—; X is CH, Y′ is        N; and m is 0, 1, 2, 3, or 4;    -   g) L is a single bond, or —C(O)—; X is CH, Y′ is N; and m is 1,        2, 3, or 4;    -   h) L is —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or —C(O)—; Cy is

-   -   and m is 0, 1, 2, 3, or 4; or    -   j) L is a single bond, or —C(O)—; Cy is

-   -   and m is 1, 2, 3, or 4;

or a pharmaceutically acceptable salt, N-oxide, solvate or prodrugthereof;

and stereoisomers, isotopic variants and tautomers thereof.

In one embodiment, L is a single bond, —CH₂—, —C(Me)H—, or —CH₂—CH₂—; Xis CH, Y′ is C—NH—C(O)—R⁶; and m is 0, 1, 2, 3, or 4.

In one embodiment, L is —C(O)—; Y′ is C—NH—C(O)—R⁶; and m is 1, 2, 3, or4.

In one embodiment, L is a single bond, —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or—C(O)—; X is N, Y′ is C—NH—C(O)—R⁶; and m is 0, 1, 2, 3, or 4.

In one embodiment, L is —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or —C(O)—; X isN, Y′ is CH; and m is 0, 1, 2, 3, or 4.

In one embodiment, L is a single bond, or —C(O)—; X is N, Y′ is CH; andm is 1, 2, 3, or 4.

In one embodiment, L is —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or —C(O)—; X isCH, Y′ is N; and m is 0, 1, 2, 3, or 4.

In one embodiment, L is a single bond, or —C(O)—; X is CH, Y′ is N; andm is 1, 2, 3, or 4.

In one embodiment, L is —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or —C(O)—; Cy is

and m is 0, 1, 2, 3, or 4.

In one embodiment, L is a single bond, or —C(O)—; Cy is

and m is 1, 2, 3, or 4.

In one embodiment, R^(4b) is halo, CN, substituted or unsubstitutedalkyl, or substituted or unsubstituted alkoxy.

In another embodiment, R^(4b) is F, Cl, CN, Me, Et, i-Pr, OMe, OEt, orCF₃.

In a particular embodiment, R^(4b) is H.

In one embodiment, with respect to the compounds of formula C-I, thecompound is according to formula C-XVIa, C-XVIb, C-XVIc, C-XVId, orC-XVIe:

wherein R⁶ is substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl; and Y is CH₂, NH, or O.

In one embodiment, with respect to the compounds of formula C-I, thecompound is according to formula C-XVIIa, C-XVIIb, C-XVIIc, C-XVIId, orC-XVIIe:

wherein R⁶ is substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl; and Y is CH₂, NH, or O.

In one embodiment, with respect to the compounds of formula C-I, thecompound is according to formula C-XVIIIa, C-XVIIIb, C-XVIIIc, C-XVIIId,or C-XVIIIe:

wherein Y is CH₂, NH, or O.

In one embodiment, with respect to the compounds of formula C-I, thecompound is according to formula C-XIXa, C-XIXb, C-XIXc, C-XIXd, orC-XIXe:

wherein Y is CH₂, NH, or O.

In one embodiment, with respect to the compounds of formula C-I, thecompound is according to formula C-XXa, C-XXb, C-XXc, C-XXd, or C-XXe:

wherein Y is CH₂, NH, or O.

In one embodiment, Y is CH₂.

In another embodiment, Y is N.

In another embodiment, Y is O.

In one embodiment, m is 1, 2, 3, or 4.

In another embodiment, m is 1 or 2.

In a particular embodiment, m is 1.

In one embodiment, each R⁵ is independently selected from halo, CN,substituted or unsubstituted alkyl, substituted or unsubstituted amino,substituted or unsubstituted acylamino, and substituted or unsubstitutedalkoxy.

In another embodiment, each R⁵ is independently selected from F, Cl, CN,Me, Et, i-Pr, OMe, OEt, —NH—C(O)R⁶, and CF₃; and R⁶ is substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

In another embodiment, m is 1; R⁵ is —NH—C(O)R⁶; and R⁶ is substitutedor unsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In another embodiment, m is 1; R⁵ is —NH—C(O)R⁶; and R⁶ is Me, Et, i-Pr,n-Pr, n-Bu, t-Bu, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, orPh.

In a particular embodiment, m is 0.

In one embodiment, R⁶ is substituted or unsubstituted alkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.

In another embodiment, R⁶ Me, Et, i-Pr, n-Pr, n-Bu, t-Bu, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, or Ph.

In one particular embodiment, R⁶ is Me, or Et.

In anther particular embodiment, R⁶ is Me.

In one embodiment, n is 1, 2, 3, or 4. In another embodiment, n is 1 or2. In a particular embodiment, n is 1. In a more particular embodiment,n is 0.

In one embodiment, each R^(4a) is independently selected from halo, CN,substituted or unsubstituted alkyl, and substituted or unsubstitutedalkoxy. In another embodiment, each R^(4a) is independently selectedfrom F, Cl, CN, Me, Et, i-Pr, OMe, OEt, and CF₃. In a particularembodiment, R^(4a) is Me, Cl, CN, or OMe. In another particularembodiment, R^(4a) is CN. In another particular embodiment, R^(4a) is at6-position of the quinoline core. In yet another particular embodiment,R^(4a) is at 7-position of the quinoline core.

In one embodiment, with respect to the compounds of formula C-I, R^(4b)is halo, CN, substituted or unsubstituted alkyl, or substituted orunsubstituted alkoxy. In another embodiment, R^(4b) is F, Cl, CN, Me,Et, i-Pr, OMe, OEt, or CF₃. In a particular embodiment, R^(4b) is H.

In one embodiment, with respect to the compounds of formula C—I-C-IIe,Cy is substituted or unsubstituted aryl. In another embodiment, Cy issubstituted or unsubstituted phenyl or naphthyl. In another embodiment,Cy is substituted or unsubstituted phenyl.

In one embodiment, with respect to the compounds of formula C—I-C-IIe,Cy is phenyl substituted with alkoxy. In one embodiment, alkoxy is OMeor OEt.

In one embodiment, with respect to the compounds of formula C—I-C-IIe,Cy is phenyl substituted with acylamino. In one embodiment, acylamino is—NHAc; Ac is acyl, and acyl is as described herein. In a particularembodiment, acylamino is —NH—C(O)-alkyl, and alkyl is substituted orunsubstituted C₁-C₄ alkyl. In a particular embodiment, alkyl issubstituted with halo, alkoxy, alkylamino, or dialkylamino. In a moreparticular embodiment, acylamino is —NH—C(O)-Me.

In one embodiment, with respect to the compounds of formula C—I-C-IIe,Cy is substituted or unsubstituted heteroaryl. In another embodiment, Cyis substituted or unsubstituted pyridyl, pyrimidinyl, or pyrazinyl. Inanother embodiment, Cy is substituted or unsubstituted pyridyl. In aparticular embodiment, Cy is unsubstituted pyridyl.

In one embodiment, with respect to the compounds of formulaC-IIIa-C-IIIe, each R⁵ is independently selected from halo, CN,substituted or unsubstituted alkyl, substituted or unsubstituted amino,substituted or unsubstituted acylamino, and substituted or unsubstitutedalkoxy. In another embodiment, each R⁵ is independently selected from F,Cl, CN, Me, Et, i-Pr, OMe, OEt, —NH—C(O)R⁶, and CF₃; and R⁶ issubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl.

In one embodiment, with respect to the compounds of formulaC-IIIa-C-IIIe, m is 1; R⁵ is —NH—C(O)R⁶; and R⁶ is substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In one embodiment, with respect to the compounds of formulaC-IIIa-C-IIIe, R⁵ is —NH—C(O)R⁶; and R⁶ is Me, Et, i-Pr, n-Pr, n-Bu,t-Bu, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or Ph.

In one embodiment, with respect to the compounds of formulaC-IIIa-C-IIIe, m is 0.

In another embodiment, with respect to the compounds of formulaC—I-C-XVe, R¹ is substituted or unsubstituted C₁-C₆ alkyl. In anotherembodiment, R¹ is Me, Et, i-Pr, n-Pr, n-Bu, or t-Bu. In anotherembodiment, R¹ is —OR²; and R² is H, substituted or unsubstituted C₁-C₆alkyl, or substituted or unsubstituted cycloalkyl. In anotherembodiment, R¹ is OMe, OEt, or O-i-Pr.

In another embodiment, with respect to the compounds of formulaC—I-C-XVe, R¹ is —NR²R³; and each R² and R³ is independently H,substituted or unsubstituted C₁-C₆ alkyl, or substituted orunsubstituted cycloalkyl.

In another embodiment, with respect to the compounds of formulaC—I-C-XVe, R¹ is —NR²R³; and each R² and R³ is independently H, Me, Et,i-Pr, n-Pr, n-Bu, or t-Bu.

In another embodiment, with respect to the compounds of formulaC—I-C-XVe, R¹ is —NR²R³; and R² is H; and R³ is Me, Et, i-Pr, n-Pr,n-Bu, or t-Bu.

In another embodiment, with respect to the compounds of formulaC—I-C-XVe, R¹ is —NR²R³; and R² is H; and R³ is Et, i-Pr, n-Pr, n-Bu, ort-Bu; each of which is substituted with hydroxyl, alkoxy, amino,alkylamino, or dialkylamino. In one embodiment, alkoxy is OMe, OEt,O-n-Pr or O-i-Pr.

In another embodiment, with respect to the compounds of formulaC—I-C-XVe, R¹ is —NR²R³; and R² and R³ are joined together to form asubstituted or unsubstituted heterocycle.

In another embodiment, with respect to the compounds of formulaC—I-C-XVe, R¹ is pyrrolidin-1-yl, piperidin-1-yl, piperizin-1-yl, ormorpholin-1-yl.

In a further aspect, the present invention provides compounds accordingto formula C-I:

wherein Cy is

R¹ is —NR²R³;

each R² and R³ is independently H, substituted or unsubstituted C₁-C₆alkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl;

each R^(4a) is independently selected from OH, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted acyl, substituted or unsubstituted acylamino, substitutedor unsubstituted alkylamino, substituted or unsubstituted alkythio,substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkylarylamino, substituted or unsubstituted amino,substituted or unsubstituted arylalkyl, sulfo, substituted sulfo,substituted sulfonyl, substituted sulfinyl, substituted sulfanyl,substituted or unsubstituted aminosulfonyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido,substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted dialkylamino, halo,nitro, and thiol; and

R^(4b) is selected from H, OH, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstituted acyl,substituted or unsubstituted acylamino, substituted or unsubstitutedalkylamino, substituted or unsubstituted alkythio, substituted orunsubstituted alkoxycarbonyl, substituted or unsubstitutedalkylarylamino, substituted or unsubstituted amino, substituted orunsubstituted arylalkyl, sulfo, substituted sulfo, substituted sulfonyl,substituted sulfinyl, substituted sulfanyl, substituted or unsubstitutedaminosulfonyl, substituted or unsubstituted alkylsulfonyl, substitutedor unsubstituted arylsulfonyl, azido, substituted or unsubstitutedcarbamoyl, carboxyl, cyano, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted dialkylamino, halo, nitro, and thiol;

the subscript n is 0, 1, 2, 3, or 4;

each R⁵ is independently selected from OH, substituted or unsubstitutedalkyl, substituted or unsubstituted alkoxy, substituted or unsubstitutedacyl, substituted or unsubstituted acylamino, substituted orunsubstituted alkylamino, substituted or unsubstituted alkythio,substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkylarylamino, substituted or unsubstituted amino,substituted or unsubstituted arylalkyl, sulfo, substituted sulfo,substituted sulfonyl, substituted sulfinyl, substituted sulfanyl,substituted or unsubstituted aminosulfonyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido,substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted dialkylamino, halo,nitro, and thiol;

R⁶ is substituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl; and

-   -   a) L is a single bond, —CH₂—, —C(Me)H—, or —CH₂—CH₂—; X is CH,        Y′ is C—NH—C(O)—R⁶; and m is 0, 1, 2, 3, or 4;    -   b) L is —C(O)—; Y′ is C—NH—C(O)—R⁶; and m is 1, 2, 3, or 4;    -   c) L is a single bond, —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or —C(O)—;        X is N, Y′ is C—NH—C(O)—R⁶; and m is 0, 1, 2, 3, or 4;    -   d) L is —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or —C(O)—; X is N, Y′ is        CH; and m is 0, 1, 2, 3, or 4;    -   e) L is a single bond, or —C(O)—; X is N, Y′ is CH; and m is 1,        2, 3, or 4;    -   f) L is —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or —C(O)—; X is CH, Y′ is        N; and m is 0, 1, 2, 3, or 4;    -   g) L is a single bond, or —C(O)—; X is CH, Y′ is N; and m is 1,        2, 3, or 4;    -   h) L is —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or —C(O)—; Cy is

-   -   and m is 0, 1, 2, 3, or 4;    -   j) L is a single bond, or —C(O)—; Cy is

-   -   and m is 1, 2, 3, or 4; or    -   k) L is —S(O)— or —S(O)₂—; and m is 0, 1, 2, 3, or 4;

or a pharmaceutically acceptable salt, N-oxide, solvate or prodrugthereof;

and stereoisomers, isotopic variants and tautomers thereof.

In a particular embodiment, -L-R¹ is —CH₂—N(Me)-CH₂CH₂OMe,—CH₂—N(Me)-CH₂CH₂CH₂OMe, —CH₂—N(Me)Et, —CH₂—N(Me)-n-Pr, —CH₂—N(Me)-i-Pr,—CH₂—N(H)—CH₂CH₂OMe, —CH₂—N(H)—CH₂CH₂CH₂OMe, —CH₂—N(H)Et,—CH₂—N(H)-n-Pr, or —CH₂—N(H)-i-Pr.

In a particular embodiment, Cy is

In one embodiment, the compound is selected from:

-   2-(4-Acetamidophenyl)-N-(2-(dimethylamino)ethyl)quinoline-4-carboxamide,-   N-(4-(4-(Morpholine-4-carbonyl)quinolin-2-yl)phenyl)acetamide,-   8-Chloro-N-cyclopropyl-2-(pyridin-2-yl)quinoline-4-carboxamide-   (6-Chloro-2-(pyridin-3-yl)quinolin-4-yl)(4-(methylsulfonyl)piperazin-1-yl)methanone,-   6-Methyl-N-(5-methylisoxazol-3-yl)-2-(pyridin-3-yl)quinoline-4-carboxamide,-   N-(4-(8-Chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)phenyl)acetamide,-   N-(5-(8-Chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)pyridin-2-yl)acetamide,-   N-(6-(8-Chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)pyridin-3-yl)acetamide,-   N-(4-(6-Chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)phenyl)acetamide,-   N-(5-(6-Chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)pyridin-2-yl)acetamide,-   N-(6-(6-Chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)pyridin-3-yl)acetamide,-   N-(4-(4-Morpholinoquinolin-2-yl)phenyl)acetamide,-   N-(4-(4-(Morpholinomethyl)quinolin-2-yl)phenyl)acetamide,-   N-(6-(4-(Morpholinomethyl)quinolin-2-yl)pyridin-3-yl)acetamide,-   N-(4-(8-Chloro-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide,-   N-(6-(8-Chloro-4-(morpholinomethyl)quinolin-2-yl)pyridin-3-yl)acetamide,-   N-(4-(4-(1-Morpholinoethyl)quinolin-2-yl)phenyl)acetamide;-   (N-(2-fluoro-4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide);-   (N-(2-chloro-4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide);-   (N-(2-methoxy-4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide);-   (N-(2-hydroxy-4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide);-   N-(2-cyano-4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide;-   (2-hydroxy-N-(4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide);-   (2-methoxy-N-(4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide);-   (2-amino-N-(4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide);-   (2-acetamido-N-(4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide);-   (N-(4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)propionamide);-   (N-(4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)isobutyramide);-   (N-(4-(7-fluoro-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide);-   (N-(4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide);-   (N-(4-(7-methyl-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide);-   (N-(4-(7-methoxy-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide);-   N-(4-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide;-   2-(4-acetamidophenyl)-4-(morpholinomethyl)quinoline-7-carboxamide;-   (N-(4-(4-(((2-hydroxyethyl)amino)methyl)quinolin-2-yl)phenyl)acetamide);-   (N-(4-(4-(((2-hydroxyethyl)(methyl)amino)methyl)quinolin-2-yl)phenyl)acetamide);-   N-(4-(4-(((2-methoxyethyl)amino)methyl)quinolin-2-yl)phenyl)acetamide);-   N-(4-(4-(((2-methoxyethyl)(methyl)amino)methyl)quinolin-2-yl)phenyl)acetamide;-   (N-(4-(4-((propylamino)methyl)quinolin-2-yl)phenyl)acetamide);-   N-(4-(4-((methyl(propyl)amino)methyl)quinolin-2-yl)phenyl)acetamide;-   N-(4-(4-((butylamino)methyl)quinolin-2-yl)phenyl)acetamide;-   (N-(4-(4-((butyl(methyl)amino)methyl)quinolin-2-yl)phenyl)acetamide);-   (N-(4-(4-(((2-(dimethylamino)ethyl)amino)methyl)quinolin-2-yl)phenyl)acetamide);-   (N-(4-(4-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)quinolin-2-yl)phenyl)acetamide);    (N-(4-(4-(((2-(methylamino)ethyl)amino)methyl)quinolin-2-yl)phenyl)acetamide);-   (N-(4-(4-((methyl(2-(methylamino)ethyl)amino)methyl)quinolin-2-yl)phenyl)acetamide);-   N-(4-(4-(3-morpholinopropyl)quinolin-2-yl)phenyl)acetamide;-   (tert-butyl    4-((2-(4-acetamidophenyl)quinolin-4-yl)methyl)piperazine-1-carboxylate);-   (N-(4-(4-((4-methylpiperazin-1-yl)methyl)quinolin-2-yl)phenyl)acetamide);-   (N-(4-(4-((4-acetylpiperazin-1-yl)methyl)quinolin-2-yl)phenyl)acetamide);-   (N-(4-(4-(piperidin-1-ylmethyl)quinolin-2-yl)phenyl)acetamide);-   4-((2-(2-methyl-1H-benzo[d]imidazol-6-yl)quinolin-4-yl)methyl)morpholine;-   (2-methyl-6-(4-(morpholinomethyl)quinolin-2-yl)benzo [d]oxazole);-   N-(2-fluoro-4-(7-fluoro-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide;-   N-(2-chloro-4-(7-fluoro-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide;-   N-(2-cyano-4-(7-fluoro-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide;-   N-(4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)-2-fluorophenyl)acetamide;-   N-(2-chloro-4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide;-   N-(4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)-2-cyanophenyl)acetamide;-   N-(2-fluoro-4-(7-methoxy-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide;-   N-(2-chloro-4-(7-methoxy-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide;-   N-(2-cyano-4-(7-methoxy-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide;-   N-(4-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)-2-fluorophenyl)acetamide;-   N-(2-chloro-4-(7-cyano-4-(morpholinomethyl)    quinolin-2-yl)phenyl)acetamide;-   N-(2-cyano-4-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide;    or-   N-(4-(7-ethoxy-4-(morpholinomethyl)quinolin-2-yl)-2-fluorophenyl)acetamide;    or a pharmaceutically acceptable salt, N-oxide, solvate or prodrug    thereof;    and stereoisomers, isotopic variants and tautomers thereof.

In another embodiment, with respect to the compound of formula C-I, thecompound is any one of the compounds listed in Tables 1, 2 or 3.

In another embodiment, with respect to the compound of formula C-I, thecompound is any one of the compounds listed in Table 1.

In another embodiment, with respect to the compound of formula C-I, thecompound is any one of the compounds listed in Table 2.

In another embodiment, with respect to the compound of formula C-I, thecompound is any one of the compounds listed in Table 3.

In a particular embodiment, the compound is any one of the compoundsselected from the group consisting of Compound number 203, 208, 214,215, 220, 221, 222, 224, 226, 227, 229, 231, 234, 238, 239, 241, 242,247 and 252.

In another particular embodiment, the compound is any one of thecompounds selected from the group consisting of Compound number 214,225, 226, 228, 229, 231, 234, 235, 236, 238, 242, 247, 250 and 260.

In another particular embodiment, the compound is any one of thecompounds selected from the group consisting of Compound number 203,208, 214, 226 and 229.

In another particular embodiment, the compound is any one of thecompounds selected from the group consisting of Compound number 214, 226and 229.

In a further aspect, this invention provides a method of treating amammal susceptible to or afflicted with a condition from among thoselisted herein, and particularly, such condition as may be associatedwith RAGE. Such conditions include, without limitation, diabetes and itscomplications, impaired wound healing, peripheral vascular disease andassociated complications, obesity, Alzheimer's disease, cancers,arthritis, nephropathy, acute and chronic inflammation, retinopathy,atherosclerosis, cardiovascular disease erectile dysfunction, tumorinvasion and metastases, neuropathy, cardio- and cerebrovascularischemia/reperfusion injury, heart attack, stroke, myocardialinfarction, ischemic cardiomyopathy, renal ischemia, sepsis, pneumonia,infection, liver injury, liver damage, Amyotrophic lateral sclerosis,neuropathy infection, allergy, asthma, organ damage from pollutants,amyloidoses asthma, pollution-associated tissue damage, skin disorders,colitis, skin aging, lupus, and others.

In one embodiment, with respect to the method of treatment, the diseaseor condition is a diabetes associated complication.

In one embodiment, with respect to the method of treatment, the diseaseor condition is atherosclerosis.

In one embodiment, with respect to the method of treatment, the diseaseor condition is arthritis.

In one embodiment, with respect to the method of treatment, the diseaseor condition is neurodegeneration.

In certain aspects, the present invention provides prodrugs andderivatives of the compounds according to the formulae above. Prodrugsare derivatives of the compounds of the invention, which havemetabolically cleavable groups and become by solvolysis or underphysiological conditions the compounds of the invention, which arepharmaceutically active, in vivo. Such examples include, but are notlimited to, choline ester derivatives and the like, N-alkylmorpholineesters and the like.

Other derivatives of the compounds of this invention have activity inboth their acid and acid derivative forms, but the acid sensitive formoften offers advantages of solubility, tissue compatibility, or delayedrelease in the mammalian organism (see, Bundgard, H., Design ofProdrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs includeacid derivatives well know to practitioners of the art, such as, forexample, esters prepared by reaction of the parent acid with a suitablealcohol, or amides prepared by reaction of the parent acid compound witha substituted or unsubstituted amine, or acid anhydrides, or mixedanhydrides. Simple aliphatic or aromatic esters, amides and anhydridesderived from acidic groups pendant on the compounds of this inventionare preferred prodrugs. In some cases it is desirable to prepare doubleester type prodrugs such as (acyloxy)alkyl esters or((alkoxycarbonyl)oxy)alkylesters. Preferred are the C₁ to C₈ alkyl,C₂-C₈ alkenyl, aryl, C₇-C₁₂ substituted aryl, and C₇-C₁₂ arylalkylesters of the compounds of the invention.

Pharmaceutical Compositions

When employed as pharmaceuticals, the compounds of this invention aretypically administered in the form of a pharmaceutical composition. Suchcompositions can be prepared in a manner well known in thepharmaceutical art and comprise at least one active compound.

Generally, the compounds of this invention are administered in apharmaceutically effective amount. The amount of the compound actuallyadministered will typically be determined by a physician, in the lightof the relevant circumstances, including the condition to be treated,the chosen route of administration, the actual compound-administered,the age, weight, and response of the individual patient, the severity ofthe patient's symptoms, and the like.

The pharmaceutical compositions of this invention can be administered bya variety of routes including oral, rectal, intraocular, transdermal,subcutaneous, intravenous, intramuscular, intraperitoneal, interdermal,directly into cerebrospinal fluid, intratracheal, and intranasal.Depending on the intended route of delivery, the compounds of thisinvention are preferably formulated as either injectable or oralcompositions or as salves, as lotions or as patches all for transdermaladministration.

The compositions for oral administration can take the form of bulkliquid solutions or suspensions, or bulk powders. More commonly,however, the compositions are presented in unit dosage forms tofacilitate accurate dosing. The term “unit dosage forms” refers tophysically discrete units suitable as unitary dosages for human subjectsand other mammals, each unit containing a predetermined quantity ofactive material calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical excipient. Typical unitdosage forms include prefilled, premeasured ampules or syringes of theliquid compositions or pills, tablets, capsules or the like in the caseof solid compositions. In such compositions, the furansulfonic acidcompound is usually a minor component (from about 0.1 to about 50% byweight or preferably from about 1 to about 40% by weight) with theremainder being various vehicles or carriers and processing aids helpfulfor forming the desired dosing form.

Liquid forms suitable for oral administration may include a suitableaqueous or nonaqueous vehicle with buffers, suspending and dispensingagents, colorants, flavors and the like. Solid forms may include, forexample, any of the following ingredients, or compounds of a similarnature: a binder such as microcrystalline cellulose, gum tragacanth orgelatin; an excipient such as starch or lactose, a disintegrating agentsuch as alginic acid, Primogel, or corn starch; a lubricant such asmagnesium stearate; a glidant such as colloidal silicon dioxide; asweetening agent such as sucrose or saccharin; or a flavoring agent suchas peppermint, methyl salicylate, or orange flavoring.

Injectable compositions are typically based upon injectable sterilesaline or phosphate-buffered saline or other injectable carriers knownin the art. As before, the active compound in such compositions istypically a minor component, often being from about 0.05 to 10% byweight with the remainder being the injectable carrier and the like.

Transdermal compositions are typically formulated as a topical ointmentor cream containing the active ingredient(s), generally in an amountranging from about 0.01 to about 20% by weight, preferably from about0.1 to about 20% by weight, preferably from about 0.1 to about 10% byweight, and more preferably from about 0.5 to about 15% by weight. Whenformulated as a ointment, the active ingredients will typically becombined with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredients may be formulated in a cream with,for example an oil-in-water cream base. Such transdermal formulationsare well-known in the art and generally include additional ingredientsto enhance the dermal penetration of stability of the active ingredientsor the formulation. All such known transdermal formulations andingredients are included within the scope of this invention.

The compounds of this invention can also be administered by atransdermal device. Accordingly, transdermal administration can beaccomplished using a patch either of the reservoir or porous membranetype, or of a solid matrix variety.

The above-described components for orally administrable, injectable ortopically administrable compositions are merely representative. Othermaterials as well as processing techniques and the like are set forth inPart 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, MackPublishing Company, Easton, Pa., which is incorporated herein byreference.

The compounds of this invention can also be administered locally to theeye for the treatment of diabetic neuropathy. Suitable compositionsinclude those administrable by eye drops, injections or the like. In thecase of eye drops, the composition can also optionally include, forexample, ophthalmologically compatible agents such as isotonizingagents, buffering agents, surfactants, stabilization agents, and otheringredients. For injection, the compound can be provided in an injectiongrade saline solution, in the form of an injectable liposome solution,slow-release polymer system or the like.

The compounds of this invention can also be administered in sustainedrelease forms or from sustained release drug delivery systems. Adescription of representative sustained release materials can be foundin Remington's Pharmaceutical Sciences.

The following formulation examples illustrate representativepharmaceutical compositions of this invention. The present invention,however, is not limited to the following pharmaceutical compositions.

Formulation 1—Tablets

A compound of the invention is admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed into240-270 mg tablets (80-90 mg of active amide compound per tablet) in atablet press.

Formulation 2—Capsules

A compound of the invention is admixed as a dry powder with a starchdiluent in an approximate 1:1 weight ratio. The mixture is filled into250 mg capsules (125 mg of active amide compound per capsule).

Formulation 3—Liquid

A compound of the invention (125 mg), sucrose (1.75 g) and xanthan gum(4 mg) are blended, passed through a No. 10 mesh U.S. sieve, and thenmixed with a previously made solution of microcrystalline cellulose andsodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate(10 mg), flavor, and color are diluted with water and added withstirring. Sufficient water is then added to produce a total volume of 5mL.

Formulation 4—Tablets

A compound of the invention is admixed as a dry powder with a drygelatin binder in an approximate 1:2 weight ratio. A minor amount ofmagnesium stearate is added as a lubricant. The mixture is formed into450-900 mg tablets (150-300 mg of active amide compound) in a tabletpress.

Formulation 5—Injection

A compound of the invention is dissolved or suspended in a bufferedsterile saline injectable aqueous medium to a concentration ofapproximately 5 mg/ml.

Formulation 6—Topical

Stearyl alcohol (250 g) and a white petrolatum (250 g) are melted atabout 75° C. and then a mixture of a compound of the invention (50 g)methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate(10 g), and propylene glycol (120 g) dissolved in water (about 370 g) isadded and the resulting mixture is stirred until it congeals.

Methods of Treatment

Types 1 and 2 diabetes are on the rise in the United States andworld-wide [1-3]. The long-term consequences of diabetes ensue from thedirect and indirect effects of hyperglycemia. Diabetes attacks themacro- and microvasculature and is well-established as a leading causeof heart attacks and stroke, blindness, renal failure, amputations, andperipheral neuropathies. The strong epidemiological links betweendiabetes and Alzheimer's disease raise the possibility that devastatingloss of quality and duration of life in the form of irreversible chronicdisease often accompany diabetes. Despite significant advances in thetreatment of hyperglycemia, definitive means to prevent thecomplications of diabetes are not yet on the immediate horizon. Indeed,rigorous control of hyperglycemia, particularly in older individuals,may be fraught with significant sequelae, such as striking hypoglycemia,seizures, cardiac ischemia and death [4-6].

The products of nonenzymatic glycation and oxidation of proteins andlipids, the advanced glycation endproducts (AGEs), form and accumulateto accelerated degrees in hyperglycemia [7]. AGEs may be detected in theplasma, urine, skin and other tissues of diabetic subjects and theirpresence has been linked to the development of complications ofdiabetes. AGEs impart their effects in part by non-receptor mediatedmechanisms, such as by cross-linking of the body's proteins,particularly those that are long-lived such as in basement membranes.AGEs also exert their effects by receptor-dependent mechanisms; thechief receptor for AGE is the receptor for AGE or RAGE. Extensiveevidence reveals that expression of RAGE, a member of the immunoglobulinsuperfamily of cell surface molecules, is increased in animal model andhuman diabetic tissues, such as in the macro- and microvascular tissues.RAGE is a multi-ligand receptor and the finding that RAGE binds at leastcertain members of the pro-inflammatory S100/calgranulin family and highmobility group box 1 (HMGB1) indicate that inflammatory mechanismscontribute integrally to the pathogenesis of complications. Indeed,non-AGE RAGE ligands also accumulate in human and animal model diabetictissues [8-9]. Once thought highly unlikely, the role of inflammation inat least certain forms/stages of diabetic complications is now widelyappreciated. Pharmacological and genetic approaches by multiplelaboratories, working independently, have provided very strong supportfor roles for RAGE in the pathogenesis of diabetic complications. Forexample, administration of antibodies to RAGE or soluble RAGE (thelatter the extracellular ligand binding domain of RAGE) or geneticdeletion of RAGE significantly reduces accelerated diabeticatherosclerosis in mice; ischemia/reperfusion injury in the diabetichearts; pathological and functional indices of nephropathy; pathologicaland functional indices of neuropathy; and improves wound healing indiabetic animals [8-9].

Accumulating evidence reveals that levels of soluble RAGEs (cell surfacecleaved RAGE and the endogenous secretory (splice variant)) may bebiomarkers of diabetes and its complications in human subjects; levelsof soluble RAGEs appear to be modulated by therapeutic interventions,thereby raising the significance of measuring these forms of circulatingRAGE.

In this direct context, the inventors and others demonstrated that thecytoplasmic domain of RAGE is essential for the impact of RAGEligand-RAGE interaction in modulation of gene expression and generationof vascular and inflammatory cell dysfunction. The cytoplasmic domain ofRAGE does not appear to exert its downstream signaling impact simply byendogenous phosphorylation; hence, the inventors sought to test thepremise that intracellular binding effectors were essential to bind tothe RAGE tail and thus facilitate engagement of intracellular signalingpathways. Toward that end, the inventors performed a yeast-two-hybridassay using the RAGE tail as “bait.” From this experimental work, theinventors discovered and published in 2008 that the cytoplasmic domainof RAGE interacts with the formin molecule, DIAPH1 and that DIAPH1 isrequired for the impact of RAGE signaling in multiple cell types such assmooth muscle cells, macrophages, cardiomyocytes and endothelial cells[10-13].

Fundamental observations link DIAPH1 to the pathological indices of RAGEsignal transduction directly relevant to diabetic complications. Thus,modulating the interaction between RAGE and DIAPH1 is desirable fortreating diseases and conditions where RAGE is implicated.

Further to the above, it will be appreciated that the compoundsdescribed herein act as modulators of RAGE binding to its intracellularligands (e.g., DIAPH1) and thereby reduce or prevent the activation ofNF-κB regulated genes, such as the cytokines IL-1 and TNF-α, andminimize the generation of oxidative stress. The ability of thecompounds described herein to antagonize or inhibit the binding ofphysiological ligands to the intracellular tail of RAGE renders themwell suited to use as therapeutic agents for treating or managingdiseases or conditions related to RAGE activity. More particularly, thequinoline compounds described herein may be used to treat, for example,diabetes complications, inflammation, neurodegeneration, obesity,cancer, ischemia/reperfusion injury, cardiovascular disease, Alzheimer'sDisease, and other diseases understood to be related to RAGE activity.Such compounds may be used to impair downstream signaling eventsresulting from, for example, AGE-RAGE interaction, which contributes todiabetic complications, S100/EN-RAGE/calgranulin-RAGE interaction, whichcontributes to inflammatory diseases, β-amyloid-RAGE interaction, whichcontributes to Alzheimer's Disease, and high mobility group box 1(HMGB1)-RAGE interaction, which contributes to, e.g., inflammation andcancer.

Diabetes and Diabetes Complications

Further to the above, the quinoline compounds described herein areuseful for managing and/or treating complications associated withdiabetes. Nonenzymatic glycoxidation of macromolecules results in theformation of advanced glycation endproducts (AGEs). The term AGEs refersto a heterogeneous group of compounds generated through thenon-enzymatic glycation or glycoxidation of proteins, lipids, andnucleic acids. More particularly, AGEs are the result of a series ofcomplex biochemical reactions that involve the formation of Amadoriproducts, glyceraldehyde-3-phosphate, and the reactive carbonylmethylglyoxal (MG). See, for example, Manigrasso et al. (2014, Trends inEndocrin Metab 25:15-22); the entire content of which, includingreferences cited therein, is incorporated herein by reference.Nonenzymatic glycoxidation of macromolecules is known to be enhanced inthe presence of hyperglycemia and other conditions associated withsystemic or local oxidant stress. It is also known to be enhanced inrenal failure and at sites of inflammation, and amongst other localesassociated with neurodegeneration, obesity, and cancer. Schmidt et al.(1995, Nature Med. 1:1002-1004), for example, have shown that AGEsaccumulate generally in the vasculature and tissues of patients withdiabetes. Other research has demonstrated that AGEs also accumulate inthe vasculature focally, as observed in the joint amyloid composed ofAGE-02-microglobulin found in patients with dialysis-related amyloidosis(Abedini et al. 2013, FEBS Lett 587:1119-1127; Miyata et al. 1993, J.Clin. Invest. 92:1243-1252; Miyata et al. 1996, J. Clin. Invest.98:1088-1094). AGE production is also directly accelerated byhyperglycemia. AGE formation is also frequently associated with anincrease in reactive oxygen species (ROS) (Fu et al. 1994, Diabetes43:676-683). Although AGEs accumulate slowly in both plasma and tissuesduring aging (Brownlee et al. 1988, N Engl J Med 318:1315-1321; Hallamet al. 2010, Aging Cell 9:776-784; Schleicher et al. 1997, J Clin Inv99:457-468), they are markedly increased in patients with diabetes(Makita et al. 1991, N Engl J Med 325:836-842).

Suitable animal models in which to study diabetes complications areknown in the art and are described in, for example, Manigrasso et al.(2014, Trends in Endocrin Metab 25:15-22); Stirban et al. (2014,Molecular Metabolism 3:94-108); Johnson et al. (2014, EJNMMI Res 4:26);Tekabe et al. (2014, Int J Mol Imaging Article Id 695391); Kaida et al.(2013, Diabetes 62:3241-3250); Tekabe et al. (2013, EJNMMi Res 3:37);Calcutt et al. (2009, Nat Rev Drug Discov 8:417-429); Dauch et al.(2013, J Neuroinflammation 10:64); Juranek et al. (2013, Diabetes62:931-943); Singh et al. (2014, Korean J Physiol Pharmacol 18:1-14);Ramasamy et al. (2012, Vascular Pharmacol 57: 160-167); Montagnani(2008, Br J Pharmacol 154:725-726); Nakamura et al. (1993, Am J Pathol143:1649-1656); Lin et al. (2003, Atherosclerosis 168:213-220); Hofmannet al. (2002, Diabetes 51:2082-2089); Lin et al. (2002, Atherosclerosis163:303-311); Vlassara et al. (1992, Proc Natl Acad Sci 89:12043-12047);Brownlee et al. (1986, Science 232:1629-1632); Li et al. (1996, ProcNatl Acad Sci 93:3902-3907); Park et al. (1998, Nature Med 4:1025-1031);Kislinger et al. (2001, Arteriosclerosis, Thrombosis, and VascularBiology 21:905-910); Bucciarelli et al. (2002, Circulation106:2827-2835); Wendt et al. (2006, Atherosclerosis 185:70-77); theentire content of each of which is incorporated herein by reference.

Diabetic complications—Heart

More particularly, animal models of human diabetes involving diabeticcomplications of the heart include those involving ex vivo isolatedperfused heart ischemia/reperfusion, left anterior descending coronaryartery ligation, and cardiac autonomic neuropathy. References describingsuch models are known in the art and described in, for example, Stableset al. (2014, Autonom Neurosci 177: 746-80), Bucciarelli et al. (2000,Circulation (Supplement) 102: #563, 11-117), and Aleshin et al. (2008,Am J Physiol Heart Circ Physiol 294: H1823-H1832); the entire content ofeach of which is incorporated herein by reference.

Diabetic Complications—Kidney

More particularly, animal models of human diabetes involving diabeticcomplications of the kidney include OVE26 mice, streptozotocin inducedanimals, Db/db mice, and nephrectomy. References describing such modelsare known in the art and described in, for example, Kaur et al. (2014,Inflammopharmacology 22:279-293), Reiniger et al. (2010, Diabetes 59:2043-2054), and Wendt et al. (2003, American Journal of Pathology162:1123-1137); the entire content of each of which is incorporatedherein by reference.

Diabetic Complications—Retinopathy

More particularly, animal models of human diabetes involving diabeticcomplications leading to retinopathy include streptozotocin inducedanimals, Db/db mice, and Akita mice. References describing such modelsare known in the art and described in, for example, Lai et al. (2013, JDiabetes Res 013:106594) and Barile et al. (2005, Invest Ophthalmol VisSci 46:2916-2924); the entire content of each of which is incorporatedherein by reference.

Diabetic Complications—Neuropathy

More particularly, animal models of human diabetes involving diabeticcomplications leading to neuropathy include Swiss Webster mice, Db/dbmice, and Sciatic nerve transection/crush. References describing suchmodels are known in the art and described in, for example, Juranek etal. (2010, Biochem Insights 2010:47-59), Juranek et al. (2013, Diabetes62: 931-943), Islam (2013, J Diabetes Res 2013:149452); the entirecontent of each of which is incorporated herein by reference.

Animal models of diabetes in general include streptozotocin inducedanimals, Akita mice, Db/db mice, and Ob/ob mice. These animal models areknown in the art and described in, for example, Park et al. (1998,Nature Medicine 4:1025-1031), Wendt et al. (2006, Atherosclerosis185:70-77), Wang et al. (2014, Curr Diabetes Rev 10: 131-145), andAcharjee et al. (2013, Can J Diabetes 37: 269-276); the entire contentof each of which is incorporated herein by reference.

Immune/Inflammatory Responses

The quinoline compounds described herein are envisioned as useful fortreating inflammation. In that inflammation is a common featureunderlying all of the diseases and conditions described herein, it isreasonable to expect that these compounds will also be efficacious inthe context of, for example, diabetes complications, obesity, cancer,ischemia/reperfusion injury, cardiovascular disease, neurodegeneration,Alzheimer's Disease, cystic fibrosis, multiple sclerosis, rheumatoidarthritis, psoriasis, atopic dermatitis, and eczema.

As alluded to above, RAGE is a receptor for many members of theS100/calgranulins, a family of closely related calcium-bindingpolypeptides that accumulate at sites of chronic immune/inflammatoryresponses, such as those observed in cystic fibrosis and rheumatoidarthritis. RAGE, moreover, is known to mediate the proinflammatoryeffects of S100/calgranulins on a variety of cells, includinglymphocytes and mononuclear phagocytes. Indeed, RAGE-ligand interactionswith, e.g., proinflammatory S100/calgranulins, high mobility group box 1(HMGB1), and/or AGEs are implicated as having a pivotal role in theinflammatory cascade in general. See, for example, Ramasamy et al.(2012, Vascular Pharmacol 57: 160-167); Andersson et al. (2011, Annu RevImmunol 29:139-162); the entire content of each of which, includingreferences cited therein, is incorporated herein by reference. Studiesusing in vitro models and in animal models of the delayed-typehypersensitivity (DTH) response, colitis in IL-10 null mice,collagen-induced arthritis, and experimental autoimmune encephalitismodels further underscore the fundamental role of RAGE-ligandinteractions in various inflammatory diseases including rheumatoidarthritis and multiple sclerosis.

RAGE is also been implicated in inflammatory diseases of the skin suchas but not limited to psoriasis, atopic dermatitis, and eczema.Psoriasis may, moreover, be accompanied by arthropathic symptoms thatare similar to those seen in rheumatoid arthritis. High levels ofpro-inflammatory cytokines, particularly IL-1 and IL-8, are detected inpsoriatic lesions. IL-8 is a chemotactic factor for neutrophils, whichare known to synthesize and secrete S100 proteins. As indicated hereinabove, S100 proteins are RAGE ligands, which interaction leads to thepropagation of immune and inflammatory responses that contribute andlead to a variety of diseases/conditions described herein. Psoriasin(S100A7), a member of the S100 gene family, is a secreted proteinisolated from psoriatic skin. Linkage of psoriasis geneticsusceptibility to distinct overexpression of S100 proteins in the skinhas, furthermore, been demonstrated (Semprini et. al. 2002, Hum. Genet.111:310-3). The compounds described herein are therefore envisioned astherapeutic agents for psoriasis in light of their ability to inhibitRAGE mediated downstream signaling.

High Mobility Group Box 1 (HMGB1)

HMGB1, which is also known as amphoterin, has dual activities. It wasoriginally characterized as a structural protein localized to thenucleus where it functions to stabilize DNA structure and modulatetranscriptional activity (Stros et al. 2010, Biochem Biophys Acta1799:101-113). HMGB1 was also later discovered to be an activelysecreted cytokine, produced by macrophages and other inflammatory cellsduring the innate immune response to invasion (Wang et al. 1999, Science285:248-251). Like other members of the proinflammatory cytokine family,biologically active HMGB1 can be expressed on the plasma membrane orreleased by activated inflammatory cells to accumulate in vivo duringinfection and injury. HMGB1 acts as an effector molecule capable ofaltering the metabolic and immunological activities of hematopoietic,epithelial, and neuronal cells. The breadth of its effector functions isreflected in its known activities, which include significant roles infever, anorexia, acute-phase responses, and vascular leakage syndrome.HMGB1 acts in synergy with other cytokines and pathogen-derivedmolecules in these diseases/conditions. The contribution of HMGB1 tothese and other pathological conditions is underscored by the numerousdemonstrations that administration of agents that specifically inhibitHMGB1 activity (antibodies, antagonist proteins, release inhibitors) toanimals with ischemia and inflammatory diseases interrupts theprogression of tissue injury and suppresses inflammatory responses intreated animals. See, Andersson et al. (2011, Annu Rev Immunol29:139-162) for a review).

The available evidence thus demonstrates that HMGB1 is a generalmediator of inflammation, implicated in a plethora of inflammatory andautoimmune diseases. In that HMGB1 is a ligand for RAGE, these findingsunderscore the role of RAGE as a general mediator of inflammation andrender apparent that targeting RAGE activity with the intent to inhibitdownstream signaling therefrom has significant promise and use of thecompounds described herein for the treatment of subjects afflicted withdiseases/conditions characterized by inflammation and/or autoimmunitywould attenuate clinical signs and symptoms of inflammation in suchsubjects.

Animal models of autoimmunity/inflammation include those involvingdelayed type hypersensitivity, rheumatoid arthritis, systemic lupuserythematosis, ulcerative colitis, Crohn's disease, psoriasis, Behcet'ssyndrome, Type 1 diabetes, vasculitis, glomerulonephritis, andsarcoidosis. Such animal models are known in the art and described in,for example, Hofmann et al. (1999, Cell 97:889-901), Hofmann et al.(2002, Genes and Immunity 3:123-135), Webb et al. (2014, BiochemPharmacol 87:121-130), Sakata et al. (2012, Exp Diabetes Res2012:256707), Goyal et al. (2014, Inflammopharmacology 22:219-233), Luet al. (2014, Life Sci 108(1):1-6), Starr et al. (2014, Aging Dis 5:126-136); the entire content of each of which is incorporated herein byreference.

Obesity

Animal models of human obesity are known in the art and involve feedingmice a 45% high fat diet or a 60% high fat diet. Such models aredescribed in, for example, Song et al. (2014, Diabetes 63(6): 1948-1965)and Aydin et al. (2014, Nutrition 30: 1-9); the entire content of eachof which is incorporated herein by reference.

Cancer

Abnormal expression of RAGE and its ligands has been reported in anumber of cancers, including prostatic, colorectal, pancreatic, lung,and oral squamous cell cancers. It is, moreover, thought that theinteraction of RAGE with its ligands contributes to cancer invasion andmetastasis. The interaction between RAGE and HMGB1 triggers theactivation of key cell signaling pathways, such as NF-κB, p38, p44/42MAPKs, and activation of these pathways contributes to cancerprogression and metastasis (Sims et al. 2010, Annu Rev Immunol28:367-388; Sparvero et al. 2009, J Transl Med 7:17; Lodgson et al.2007, Curr Mol Med 7:777-789; Kuniyasu et al. 2003, Oncol Rep10:445-448; Kuniyasu et al. 2003, Int J Cancer 104:722-727; Sasahira etal. 2005, Virchows Arch 446:411-415; Kuniyasu et al. 2005, Am J Pathol166:751-760; Kuniyasu et al. 2004, Pathobiology 71:129-136; Sasahira etal. 2007, Virchows Arch 450:287-295; Kuniyasu et al. 2002, J Pathol196:163-170; the entire content of each of which is incorporated hereinby reference). Further to the above, Rai et al. (2012, J Exp Med209:2339-2350) and Arumugam et al. (2012, Clin Canc Res 18:4356-4364),for example, describe animal model systems in which the contribution ofRAGE to various cancers has been investigated and validated.

Further to the above, RAGE and its ligand HMGB1 are believed to play animportant role in prostate cancer. Indeed, Zhao et al. (2014, Am JCancer Res 4:369-377) addressed the significance of these effectormolecules in a retrospective study designed to inves-tigate theexpression of RAGE and HMGB1 and their clinical impact on prostatecancer progression and prognosis. The expression of RAGE and HMGB1 wasassessed by immunohistochemistry in cancer lesions from 85 confirmedprostate cancer cases. Zhao et al. demonstrated that there is a strongcorrelation between RAGE and HMGB1 expression (P<0.001) and theexpression of RAGE, HMGB1 and their co-expression were all associatedwith advanced tumor clinical stage (P<0.05 for all). RAGE expression wasalso associated with the prostate specific antigen (PSA) level(P=0.014). Co-expression of RAGE and HMGB1 was also associated with pooroverall survival in patients with stage III and IV prostate cancer(P=0.047). These results suggest that the expression of RAGE and HMGB1is associated with progression and poor prognosis of prostate cancer.RAGE and HMGB1 are, therefore, proposed to be molecular targets fornovel forms of therapy for prostate cancer.

Tumors/Tumorigenesis

Animal models for various forms of human cancers are known in the artand include those recapitulating aspects of human lung cancer, melanoma,colon cancer, pancreatic cancer, and breast cancer and bio-models ofcancer for in silico screening. Such animal models are known in the artand are described in, for example, Taguchi et al. (2000, Nature405:354-360), Arumugam et al. (2004, Journal of Biological Chemistry279:5059-5065), Huang et al. (2006, Surgery 139:782-788), Huang et al.(2006, Surgery 139:782-788), Fuentes et al. (2007, Dis Colon Rectum50:1230-1240), Arumugam et al. (2012, Clin Cancer Res 18: 4356-4364), Yuet al. (2014, J Gastric Cancer 14:67-86), Fleet (2014, Am J PhysiolGastrointest Liver Physiol. 307(3):G249-59), Lindner (2014, Semin Oncol41: 146-155), Wang et al. (2014, Biofabrication 6(2):022001), Budhu etal. (2014, Curr Opin Genet Dev 24: 46-51, 2014); the entire content ofeach of which is incorporated herein by reference.

Ischemia/Reperfusion Injury

In, for example, animal models of hind limb ischemia in mice with orwithout diabetes, suppressing RAGE ligands has led to improvement ofangiogenic response to limb ischemia. See, for example, Tamarat et al.(2003, Proc Natl Acad Sci 100:14); Goova et al. (2001, Am J Pathol159:513-525); Tekabe et al. (2010, J Nuc Med 51:92-97); Tekabe et al.(2013, EJNMMi Res 3:37); Bucciarelli et al. (2008, Diabetes57:1941-1951); Shang et al. (2010, PLoS 5:e10092); Ma et al. (2009, JCell Mol Med 13:1751-1764); the entire content of each of which isincorporated herein by reference.

Erectile Dysfunction

Relaxation of the smooth muscle cells in the cavernosal arterioles andsinuses results in increased blood flow into the penis, raising corpuscavernosum pressure to culminate in penile erection. Nitric oxide isconsidered the principle stimulator of cavernosal smooth musclerelaxation (See Wingard et al. (2001, Nature Medicine 7:119-122). Inthat RAGE activation produces oxidants via an NADH oxidase-like enzyme(Yan et al. 1994, J. Biol. Chem. 269:9889-9887), it is thought tosuppress nitric oxide circulation. Inhibiting activation of RAGEsignaling pathways is, therefore, predicted to attenuate oxidantgeneration. Inhibition of RAGE-mediated activation of Rho-kinases isalso predicted to enhance and stimulate penile erection independently ofnitric oxide. Accordingly, compounds such as those described herein thatact to inhibit downstream RAGE signaling may be used to advantage topromote and facilitate penile erection.

Respiratory Diseases

Patients with chronic obstructive pulmonary disease exhibit increasedRAGE expression in the lung and elevated soluble RAGE levels in thebronchial alveolar fluid (Yan et al. 2003, Nature Med 9:287-293; Miniatiet al. 2011, Respir Res 12:37). Increased RAGE receptor and ligandlevels have also been detected in asthmatic patients (Watanabe et al.2010, Respir Med 105:519-525), indicating an active role for RAGE inlung inflammation. See also Wu et al. (2013, Mol Cell Biochem380:249-257); Sukkar et al. (2012, Br J Pharmacol 167:1161-1176).

Furthermore, in severe exacerbations of asthma there is an intense,mechanistically heterogeneous inflammatory response involving neutrophiland eosinophil accumulation and activation. Neutrophils are, moreover, asignificant source of S100 proteins, key ligands for RAGE implicated inthe propogation of the immune response and inflammation as describedherein above. Accordingly, inhibitors of RAGE downstream signaling wouldbe expected to be efficacious in the treatment of asthma. In that thepropagation step in the immune response in the lung driven by S100-RAGEinteraction is thought to lead to the activation and/or recruitment ofinflammatory cells, such as neutrophils, which are significant sourcesof damaging proteases in chronic obstructive pulmonary diseases such asemphysema, the compounds described herein that act as RAGE inhibitorscan be used to treat chronic obstructive pulmonary diseases.

Animal models for assessing the therapeutic potential of compoundsdescribed herein in the context of respiratory disease (e.g., asthma)are presented in, for example, Akirav et al. (2014, PLoS One9:e95678);and Constant et al. (2002, J Clin Invest 110:1441-1448); the entirecontent of each of which is incorporated herein by reference.

Amyloidoses

Compounds described herein are also envisioned as useful for treatingamyloidoses and Alzheimer's Disease (AD). RAGE is known to bind β-sheetfibrillar material and deposition of amyloid has been shown to enhanceexpression of RAGE. The brains of AD patients exhibit increasedexpression of RAGE in neurons and glia (Yan et al. 1996, Nature382:685-691). Binding of Aβ-RAGE on microglia activates these cells, asreflected by increased motility and expression of cytokines, whereasbinding of Aβ-RAGE on neurons initially activates the cells, butultimately leads to cytotoxicity. Inhibition of RAGE-amyloid interactiondecreases expression of cellular RAGE and cell stress markers (as wellas NF-κB activation) and diminishes amyloid deposition (Yan et al. 2000,Nat. Med. 6:643-651). These findings suggest that a role forRAGE-amyloid interaction exists, both with respect to perturbation ofcellular properties in an environment enriched for amyloid at earlystages of disease and progressively during the course of disease asamyloid accumulates.

Neurodegeneration

Animal models of human neurodegenerative diseases are known and includemouse models of Alzheimer's Disease, humanized mouse models ofAmyotrophic lateral sclerosis, and mouse models of Huntington's disease.Such animal models are described in, for example, Millington et al.(2014, Biomed Res Inst 2014:309129), Yan et al. (1996, Nature382:685-691), Yan et al. (1997, Proc. Natl. Acad. Sci. 94:5296-5301),Bard et al. (2014, J Biomol Screen 19: 191-204), Neha et al. (2014, LifeSci 109(2):73-86), and Turner et al. (2013, Amyotroph Lateral SclerFrontotemporal Degener. 14 Suppl 1:19-32); the entire content of each ofwhich is incorporated herein by reference.

Atherosclerosis

Examples of animal models of human atherosclerotic disease includeapolipoprotein E null mice and Low Density Lipoprotein Receptor nullmice. See, for example, Kapourchali et al. (2014, World J Clin Cases 2:126-132), Harja et al. (2008, J. Clin. Invest. 1118: 183-194), Nagareddyet al. (2013, Cell Metab 17: 695-708); the entire content of each ofwhich is incorporated herein by reference.

In light of that which is understood in the art and described hereinregarding the prominent role of RAGE in diseases/conditionscharacterized by acute and chronic inflammation, methods are presentedherein for treating such diseases/conditions, including but not limitedto diabetic complications, ischemia, skin inflammation (e.g., psoriasisand atopic dermatitis), lung inflammation (e.g., asthma and chronicobstructive pulmonary disease), vascular permeability, nephropathy,atherosclerosis, retinopathy, Alzheimer's Disease, erectile dysfunction,and tumor invasion and/or metastasis, which methods compriseadministering to a subject in need thereof a compound described hereinin a therapeutically effective amount. In a particular embodiment, atleast one compound described herein is utilized, either alone or incombination with one or more known therapeutic agents. In a furtherparticular embodiment, the present invention provides a method fortreating RAGE mediated human diseases, wherein treatment alleviates oneor more symptoms resulting from that disorder, the method comprisingadministration to a human in need thereof a therapeutically effectiveamount of a compound described herein.

In vitro assays relating to RAGE-mediated diseases and animal modelsystems thereof are described in US2012/0088778, US2010/0254983,US2010/0119512, U.S. Pat. No. 7,361,678, WO2007/089616, andUS2010/0249038, the entire content of each of which is incorporatedherein by reference.

Further to the above, the present compounds are modulators ofinteraction between RAGE and RAGE ligands and are used as therapeuticagents for the treatment of conditions in mammals that are causallyrelated or attributable to RAGE activity. Accordingly, the compounds andpharmaceutical compositions of this invention find use as therapeuticsfor preventing and/or treating a variety of conditions related to, forexample, diabetes complications in mammals, including humans.

In a method of treatment aspect, this invention provides a method oftreating a mammal susceptible to or afflicted with a conditionassociated with diabetes complications, Alzheimer's disease, cancers,arthiritis, nephropathy, acute and chronic inflammation, retinopathy,atherosclerosis, erectile dysfunction, tumor invasion and metastasis,and others, which method comprises administering an effective amount ofone or more of the pharmaceutical compositions just described.

In additional method of treatment aspects, this invention providesmethods of treating a mammal susceptible to or afflicted with aninflammatory condition causally related or attributable to RAGEactivity. Such condition and disorders include, without limitation,diabetes and its complications, impaired wound healing, peripheralvascular disease and associated complications, obesity, Alzheimer'sdisease, cancers, arthritis, nephropathy, acute and chronicinflammation, retinopathy, atherosclerosis, cardiovascular disease,erectile dysfunction, tumor invasion and metastases, neuropathy, cardio-and cerebrovascular ischemia/reperfusion injury, heart attack, stroke,myocardial infarction, ischemic cardiomyopathy, renal ischemia, sepsis,pneumonia, infection, liver injury, liver damage, Amyotrophic lateralsclerosis, neuropathy infection, allergy, asthma, organ damage frompollutants, amyloidoses asthma, pollution-associated tissue damage, skindisorders, colitis, skin aging, lupus, and others. Such methods compriseadministering an effective condition-treating or condition-preventingamount of one or more of the pharmaceutical compositions just described.

As a further aspect of the invention there is provided the presentcompounds for use as a pharmaceutical especially in the treatment orprevention of the aforementioned conditions and diseases. Also providedherein is the use of the present compounds in the manufacture of amedicament for the treatment or prevention of one of the aforementionedconditions and diseases.

Injection dose levels range from about 0.1 mg/kg/hour to at least 10mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kgor more may also be administered to achieve adequate steady statelevels. The maximum total dose is not expected to exceed about 2 g/dayfor a 40 to 80 kg human patient.

For the prevention and/or treatment of long-term conditions, such as,e.g., arthritis, diabetes, or asthma, the regimen for treatment usuallystretches over many months or years, so oral dosing is preferred forpatient convenience and tolerance. With oral dosing, one to five andespecially two to four and typically three oral doses per day arerepresentative regimens. Using these dosing patterns, each dose providesfrom about 0.01 to about 20 mg/kg of the compound of the invention, withpreferred doses each providing from about 0.1 to about 10 mg/kg andespecially about 1 to about 5 mg/kg.

Transdermal doses are generally selected to provide similar or lowerblood levels than are achieved using injection doses. Modes ofadministration suitable for mucosal sites are also envisioned herein andinclude without limitation: intra-anal swabs, enemas, intranasal sprays,and aerosolized or vaporized compounds and/or compositions for deliveryto the lung mucosa. One of skill in the art would choose an appropriatedelivery mode/s based on a variety of parameters, including the organ ortissue site in a patient with a disease or condition that is mostseverely affected by the disease or condition.

When used to prevent the onset of an inflammatory condition orautoimmune disorder, the compounds of this invention will beadministered to a patient at risk for developing the condition ordisorder, typically on the advice and under the supervision of aphysician, at the dosage levels described above. Patients at risk fordeveloping a particular condition generally include those that have afamily history of the condition, or those who have been identified bygenetic testing or screening to be particularly susceptible todeveloping the condition.

The compounds of this invention can be administered as the sole activeagent or they can be administered in combination with other agents,including other compounds that demonstrate the same or a similartherapeutic activity and are determined to safe and efficacious for suchcombined administration.

General Synthetic Procedures

The quinoline compounds of this invention may be purchased from variouscommercial sources or can be prepared from readily available startingmaterials using the following general methods and procedures. It will beappreciated that where typical or preferred process conditions (i.e.,reaction temperatures, times, mole ratios of reactants, solvents,pressures, etc.) are given, other process conditions can also be usedunless otherwise stated. Optimum reaction conditions may vary with theparticular reactants or solvent used, but such conditions can bedetermined by one skilled in the art by routine optimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and P. G. M. Wuts, ProtectingGroups in Organic Synthesis, Second Edition, Wiley, New York, 1991, andreferences cited therein.

The compounds of the invention may be prepared from known orcommercially available starting materials and reagents by one skilled inthe art of organic synthesis.

For example, exemplary compounds of formula C—I can be preparedfollowing the methods described in Scheme 1.

The Suzuki coupling can be carried out under generic Suzuki conditions,for example, using common boron reagents and in the presence of Pdcatalysts (Hirdate, et al., Jpn Kokai Koho, 2008179621).

More information on Suzuki coupling can be found in: Miyaura, Norio;Yamada, Kinji; Suzuki, Akira (1979). “A new stereospecificcross-coupling by the palladium-catalyzed reaction of 1-alkenylboraneswith 1-alkenyl or 1-alkynyl halides”. Tetrahedron Letters 20 (36):3437-3440; Miyaura, Norio; Suzuki, Akira (1979). “Stereoselectivesynthesis of arylated (E)-alkenes by the reaction of alk-1-enylboraneswith aryl halides in the presence of palladium catalyst”. Chem. Comm.(19): 866-867; and Miyaura, Norio; Suzuki, Akira (1995).“Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds”.Chemical Reviews 95 (7): 2457-2483.

Materials and Methods:

All reactions were conducted under an atmosphere of dry nitrogen unlessspecified otherwise. TLC plates were visualized with u.v. light. Flashchromatography refers to column chromatography over silica gel (40-60μm) using glass columns. Alternatively, automated chromatography wasperformed using ISCO, Biotage SP1 or Biotage Isolera systems with u.v.detection at 220 or 254 nm and employing ISCO/Biotage normal phase orreverse phase silica cartridges. Further details can be found under therelevant experimental procedure.

The following system was used for LCMS: Agilent 1260(binary pump), Haloanalytical column C18, 2.7 μm, 4.6×50 mm, 45° C., 1 μL injection volume,1.8 mL/min, with a gradient of acetonitrile in 0.05% aqueous formic acidaccording to the following timings:

Time (min) Acetonitrile (0.05% FA) (%) H₂O (0.05% FA) (%) 0.00 5 95 1.0095 5 2.00 95 5

The chemical structure of the target compounds were confirmed by ¹H NMRand LC-MS and purity >95% determined using UPLC at 214 & 254 nm. NMRspectra were measured with a Bruker spectrometer operating at 400 MHz(¹H), 376 MHz (¹⁹F) or 100 MHz (¹³C). Solvents used for purification arespecified in the experimental procedures for each compound. Thefollowing systems were used for UPLC (no mass spectrometry): WatersH-Class (quaternary pump), Waters ACQUITY BEH C18 1.7 μm, 2.1×50 mm, 0.5mL/min, 40° C.; gradient 5-95% acetonitrile in 0.1% aqueoustrifluoroacetic acid over 2 min, then hold 95% acetonitrile 0.7 min.

The following systems were used for prep-HPLC: Waters H-Class(quaternary pump), Gemini 5u C18 150×21.2 mm, 20 ml/min, 40° C.

Gradient Time ACN H₂O (with or method (min) (%) without 0.1% FA) 0 2 982 2 98 4 30 70 12 40 60 14.5 95 5 15 2 98 17 2 98

Example 1 Methyl 2-(4-acetamidophenyl)quinoline-4-carboxylate

Step A: 2-(4-Aminophenyl)quinoline-4-carboxylic acid (2)

A solution of 1-(4-aminophenyl)ethanone (2.74 g, 20.25 mmol) in ethanol(10 mL) was added slowly to a solution of indoline-2,3-dione (1) (2 g,13.6 mmol) in 6 M aqueous KOH solution (10 mL) at 100° C. The reactionwas monitored by LCMS until the staring material consumed. Then thereaction mixture was concentrated to remove ethanol, the residue wasdiluted with water (20 mL), the pH value of the mixture was acidified to5 by adding 1M aqueous HCl solution. The precipitate was filtered togive the desired product (1.5 g, 42%) as an orange solid.

LC-MS: (M+H)⁺ 265.1

Step B: 2-(4-Acetamidophenyl)quinoline-4-carboxylic acid (3)

To a solution of 2-(4-aminophenyl)quinoline-4-carboxylic acid (1.0 g,3.79 mmol) in DCM (20 mL) was added acetic anhydride (773 mg, 7.6 mmol),Et₃N (1.15 g, 11.37 mmol) at 0° C. and the reaction mixture was stirredat room temperature for 2 h. The reaction mixture was quenched withwater (100 ml) and extracted with DCM (50 mL×2). The combined organiclayers were concentrated and purified by silica gel columnchromatography with ethyl acetate to give the product (800 mg, 69%) as ayellow solid.

LC-MS: (M+H)⁺ 307.1

Step C: Methyl 2-(4-acetamidophenyl)quinoline-4-carboxylate (Example 1)

A mixture of 2-(4-acetamidophenyl)quinoline-4-carboxylic acid (280 mg,0.91 mmol), MeOH (45 mg, 1.37 mmol), HOBt (245.7 mg, 1.82 mmol), EDCI(347.6 mg, 1.82 mmol) and DIPEA (352.1 mg, 2.73 mmol) in DCM (15 mL) wasstirred at room temperature for 16 h. Water (50 mL) was added to thereaction mixture and extracted with ethyl acetate (45 mL×3). Thecombined organic layers were concentrated and purified by silica gelcolumn chromatography with ethyl acetate to give the product (100 mg,34%) as a white solid. LC-MS: (M+H)⁺ 321.1

¹H NMR (400 MHz, MeOD) δ 8.71 (d, J=7.9 Hz, 1H), 8.43 (s, 1H), 8.22-8.14(m, 3H), 7.82 (m, 3H), 7.70-7.63 (m, 1H), 4.09 (s, 3H), 2.20 (s, 3H).

Example 2 (Table 1, Compound 4)

2-(4-Acetamidophenyl)-N-(2-(dimethylamino)ethyl)quinoline-4-carboxamide

A mixture of 2-(4-acetamidophenyl)quinoline-4-carboxylic acid (3,Example 1, step B) (280 mg, 0.91 mmol), N,N-dimethylethane-1,2-diamine(121 mg, 1.37 mmol), HOBt (245.7 mg, 1.82 mmol), EDCI (347.6 mg, 1.82mmol) and DIPEA (352.1 mg, 2.73 mmol) in DCM (15 mL) was stirred at roomtemperature t for 16 h. Water (50 mL) was added to the reaction mixtureand extracted with DCM (30 mL×2). The combined organic layers wereconcentrated and purified by silica gel column chromatography with ethylacetate to give the product (110 mg, 32%) as a white solid.

LC-MS: (M+H)⁺ 377.2

¹H NMR (400 MHz, MeOD) δ 8.29-8.11 (m, 5H), 7.85-7.75 (m, 3H), 7.67-7.59(m, 1H), 3.73 (t, J=6.5 Hz, 2H), 2.88 (t, J=6.5 Hz, 2H), 2.55 (s, 6H),2.20 (s, 3H).

Example 3 (Table 1, Compound 5)N-(4-(4-(Morpholine-4-carbonyl)quinolin-2-yl)phenyl)acetamide

N-(4-(4-(Morpholine-4-carbonyl)quinolin-2-yl)phenyl)acetamide

A mixture of 2-(4-acetamidophenyl)quinoline-4-carboxylic acid (3,Example 1, step B) (180 mg, 0.59 mmol), morpholine (100 mg, 1.17 mmol),HOBt (120 mg, 0.89 mmol), EDCI (170 mg, 0.89 mmol) and DIPEA (228 mg,1.77 mmol) in DCM (15 mL) was stirred at room temperature for 16 h.Water (50 mL) was added to the reaction mixture and extracted with DCM(30 mL×3). The combined organic layers were concentrated and purified bysilica gel column chromatography with ethyl acetate to give the product(90 mg, 41%) as a white solid.

LC-MS: (M+H)⁺ 376.2

¹H NMR (400 MHz, MeOD) δ 8.19 (t, J=8.3 Hz, 3H), 8.02 (s, 1H), 7.86 (dd,J=17.3, 8.6 Hz, 2H), 7.79 (d, J=8.7 Hz, 2H), 7.67 (t, J=7.6 Hz, 1H),3.98-3.84 (m, 4H), 3.58 (m, 2H), 3.32-3.20 (m, 2H), 2.19 (s, 3H).

Example 4 8-Chloro-N-cyclopropyl-2-(pyridin-2-yl)quinoline-4-carboxamide

Step A: 8-Chloro-2-(pyridin-2-yl)quinoline-4-carboxylic acid (5)

A solution of 1-(pyridin-2-yl)ethanone (1.0 g, 8.3 mmol) in ethanol (10mL) was added slowly to a solution of 7-chloroindoline-2,3-dione (4) (1g, 5.5 mmol) in 6M aqueous KOH (10 mL) at 100° C. The reaction wasmonitored by LCMS until the staring material consumed. Then the reactionmixture was concentrated to remove ethanol, the residue was diluted withwater (10 mL), the pH value of the mixture was acidified to pH=5 byadding 1M aqueous HCl solution. The precipitate was filtered to give thedesired product (400 mg, 26%) as an orange solid.

LC-MS: (M+H)⁺ 285.1

Step B: 8-Chloro-N-cyclopropyl-2-(pyridin-2-yl)quinoline-4-carboxamide,Example 4

A mixture of 8-chloro-2-(pyridin-2-yl)quinoline-4-carboxylic acid (5from Step A) (200 mg, 0.7 mmol), cyclopropanamine (60 mg, 1.05 mmol),HOBt (189 mg, 1.4 mmol), EDCI (267 mg, 1.4 mmol) and DIPEA (362 mg, 2.8mmol) in DCM (15 mL) was stirred at room temperature for 16 h. Water (50mL) was added to the reaction mixture and extracted with DCM (30 mL×2).The combined organic layers were concentrated and purified by silica gelcolumn chromatography with petroleum ether/ethyl acetate (1:1) to givethe product (100 mg, 44%) as a white solid.

LC-MS: (M+H)⁺324.1

¹H NMR (400 MHz, DMSO) δ 9.04 (d, J=4.2 Hz, 1H), 8.83-8.77 (m, 1H),8.72-8.66 (m, 1H), 8.60 (s, 1H), 8.15 (dd, J=8.4, 1.2 Hz, 1H), 8.12-8.05(m, 2H), 7.68 (m, 1H), 7.60 (m, 1H), 3.05-2.94 (m, 1H), 0.78 (m, 2H),0.69-0.61 (m, 2H).

Example 5(6-Chloro-2-(pyridin-3-yl)quinolin-4-yl)(4-(methylsulfonyl)piperazin-1-yl)methanone

Step A: tert-Butyl 4-(methylsulfonyl)piperazine-1-carboxylate (7)

To a solution of tert-butyl piperazine-1-carboxylate (6) (1 g, 5.4 mmol)in DCM (10 mL) was added Et₃N (1.1 g, 10.8 mmol) and MsCl (923 mg, 8.1mmol) at 0° C., and the reaction mixture was stirred at room temperaturefor 2 h. Water (50 ml) was added to the reaction mixture and extractedwith DCM (50 mL×2). The combined organic layers were concentrated andpurified by silica gel column chromatography with petroleum ether/ethylacetate (5:1) to give the product (900 mg, 63%) as a light yellow solid.

LC-MS: (M+H)⁺265.1

Step B: 1-(Methylsulfonyl)piperazine (8)

A solution of tert-butyl 4-(methylsulfonyl)piperazine-1-carboxylate (7from Step A) (900 mg, 3.4 mmol) in 4M HCl in dioxane (10 mL) was stirredat room temperature for 1 h. The reaction mixture was concentrated togive the crude product (410 mg) as a light yellow solid which was usedinto next step without purification.

LC-MS: (M+H)⁺165.1

Step C: 6-Chloro-2-(pyridin-3-yl)quinoline-4-carboxylic acid (10)

5-Chloroindoline-2,3-dione (9) (1 g, 5.5 mmol) in 6M aqueous KOH (10 mL)was heated to 100° C. To this solution was added a solution of1-(pyridin-3-yl)ethanone (1 g, 8.3 mmol) in ethanol (10 mL) slowly. Theresulting reaction mixture was stirred at 100° C. until LCMS showed thestaring material consumed. Then the reaction mixture was concentrated toremove ethanol, the residue was diluted with water (10 mL), the pH valueof the mixture was acidified to 5 by adding 1M aqueous HCl solution. Theprecipitate was filtered to give the desired product (0.5 g, 32%) as anorange solid.

LC-MS: (M+H)⁺ 285.1

Step D:(6-Chloro-2-(pyridin-3-yl)quinolin-4-yl)(4-(methylsulfonyl)piperazin-1-yl)methanone

A mixture of 6-chloro-2-(pyridin-3-yl)quinoline-4-carboxylic acid (10form Step C) (200 mg, 0.7 mmol), 1-(methylsulfonyl)piperazine (8, fromStep B) (172 mg, 1.05 mmol), HOBt (190 mg, 1.4 mmol), EDCI (268 mg, 1.4mmol) and DIPEA (362 mg, 2.8 mmol) in DCM (15 mL) was stirred at roomtemperature for 16 h. Water (50 mL) was added to the reaction mixtureand extracted with DCM (30 mL×3). The combined organic layers wereconcentrated and purified by silica gel column chromatography withpetroleum ether/ethyl acetate (1:1) to give to give the product (110 mg,36%) as a white solid.

LC-MS: (M+H)⁺ 431.1

¹H NMR (400 MHz, CDCl₃) δ 9.35 (s, 1H), 8.75 (d, J=4.0 Hz, 1H), 8.53 (d,J=8.0 Hz, 1H), 8.18 (d, J=8.9 Hz, 1H), 7.83 (s, 1H), 7.81-7.74 (m, 2H),7.51 (dd, J=7.8, 4.8 Hz, 1H), 4.10 (d, J=27.4 Hz, 2H), 3.47 (d, J=4.2Hz, 2H), 3.38 (d, J=4.6 Hz, 2H), 3.16 (d, J=17.6 Hz, 2H), 2.86 (s, 3H).

Example 66-Methyl-N-(5-methylisoxazol-3-yl)-2-(pyridin-3-yl)quinoline-4-carboxamide

Step A: 6-Methyl-2-(pyridin-3-yl)quinoline-4-carboxylic acid (12)

A solution of 1-(pyridin-3-yl)ethanone (1.12 g, 9.3 mmol) in ethanol (10mL) was added slowly to a solution of 5-methylindoline-2,3-dione (11) (1g, 6.2 mmol) in 6 M aqueous KOH (10 mL) at 100° C. The reaction wasmonitored by LCMS until the staring material consumed. Then the reactionmixture was concentrated to remove ethanol, the residue was diluted withwater (10 mL), the pH value of the mixture was acidified to 5 by adding1M aqueous HCl solution. The precipitate was filtered to give thedesired product (300 mg, 18%) as an orange solid.

LC-MS: (M+H)⁺ 265.

Step B:6-Methyl-N-(5-methylisoxazol-3-yl)-2-(pyridin-3-yl)quinoline-4-carboxamide

A mixture of 6-methyl-2-(pyridin-3-yl)quinoline-4-carboxylic acid (12from Step A) (200 mg, 0.75 mmol), 5-methylisoxazol-3-amine (112 mg, 1.13mmol), HOBt (203 mg, 1.5 mmol), EDCI (286 mg, 1.5 mmol) and DIPEA (290mg, 2.25 mmol) in DCM (15 mL) was stirred at room temperature for 16 h.Water (50 mL) was added to the reaction mixture and extracted with DCM(30 mL×3). The combined organic layers were concentrated and purified bysilica gel column chromatography with petroleum ether/ethyl acetate(1:1) to give the product (100 mg, 39%) as a white solid.

LC-MS: (M+H)⁺ 345.1

¹H NMR (400 MHz, MeOD) δ 9.42 (d, J=1.5 Hz, 1H), 8.74-8.61 (m, 2H), 8.26(s, 1H), 8.14 (d, J=8.7 Hz, 1H), 8.03 (s, 1H), 7.74 (dd, J=8.7, 1.7 Hz,1H), 7.65 (dd, J=7.7, 5.1 Hz, 1H), 6.88 (s, 1H), 2.59 (s, 3H), 2.51 (s,3H).

Example 7 (Table 2, Compound 101)N-(4-(8-Chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)phenyl)acetamide

Step A: 2-(4-Aminophenyl)-8-chloroquinoline-4-carboxylic acid (13)

A solution of 1-(4-aminophenyl)ethanone (2.74 g, 20.25 mmol) in ethanol(20 mL) was added slowly to a solution of 7-chloroindoline-2,3-dione (4)(2.4 g, 13.5 mmol) in 6M aqueous KOH (20 mL) at 100° C. The reaction wasmonitored by LCMS until the staring material consumed. Then the reactionmixture was concentrated to remove ethanol, the residue was diluted withwater (10 mL), the pH value of the mixture was acidified to 5 by adding1M aqueous HCl solution. The precipitate was filtered to give thedesired product (1.8 g, 45%) as an orange solid.

LC-MS: (M+H)⁺299.1

Step B: 2-(4-Acetamidophenyl)-8-chloroquinoline-4-carboxylic acid (14)

To a solution of 2-(4-aminophenyl)-8-chloroquinoline-4-carboxylic acid(13 from step A) (1.1 g, 3.79 mmol) in DCM (20 mL) was added aceticanhydride (773 mg, 7.6 mmol), Et₃N (1.15 g, 11.37 mmol) at 0° C. Themixture was stirred at room temperature for 2 h. The resulting mixturewas quenched with Water (50 ml), extracted with DCM (30 mL×3). Thecombined organic layers were concentrated and purified by silica gelcolumn chromatography with ethyl acetate to give the product (830 mg,64%) as a light yellow solid.

LC-MS: (M+H)⁺ 341.1

Step C:N-(4-(8-Chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)phenyl)acetamide

A mixture of 2-(4-acetamidophenyl)-8-chloroquinoline-4-carboxylic acid(155 mg, 0.46 mmol), morpholine (60 mg, 0.68 mmol), HOBt (123 mg, 0.91mmol), EDCI (174 mg, 0.91 mmol) and DIPEA (176 mg, 1.37 mmol) in DCM (15mL) was stirred at room temperature for 16 h. Water (50 mL) was added tothe reaction mixture and extracted with DCM (30 mL×3). The combinedorganic layers were concentrated and purified by silica gel columnchromatography with ethyl acetate to give the product (100 mg, 54%) as awhite solid.

LC-MS: (M+H)⁺410.1

¹H NMR (400 MHz, CDCl₃) δ 8.25 (d, J=8.5 Hz, 2H), 7.88 (d, J=7.4 Hz,1H), 7.84 (s, 1H), 7.71 (dd, J=16.7, 8.0 Hz, 3H), 7.48 (t, J=7.9 Hz,1H), 7.40 (s, 1H), 4.10-4.00 (m, 1H), 3.93-3.83 (m, 3H), 3.53 (m, 2H),3.21 (m, 2H), 2.22 (s, 3H).

Example 8 (Table 2, Compound 102)N-(5-(8-Chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)pyridin-2-yl)acetamide

Step A: 1-(6-Aminopyridin-3-yl)ethanone (16)

A solution of 1-(6-chloropyridin-3-yl)ethanone (15) (2 g, 13 mmol) inNH₄OH (30 ml) was heated and stirred at 130° C. for 16 h. The reactionmixture was then cooled to room temperature; solvent was concentrated togive the desired product (1.5 g, 84%) as a white solid which was usedinto next step without purification.

LC-MS: (M+H)⁺ 137.1

Step B: 2-(6-Aminopyridin-3-yl)-8-chloroquinoline-4-carboxylic acid (17)

A solution of 1-(6-aminopyridin-3-yl)ethanone (16, step A) (1.5 g, 11.0mmol) in ethanol (10 mL) was added slowly to a solution of7-chloroindoline-2,3-dione (4) (1.66 g, 9.17 mmol) in 6M aqueous KOH (10mL) at 100° C. The reaction was monitored by LCMS until the staringmaterial consumed. Then the reaction mixture was concentrated to removeethanol, the residue was diluted with water (10 mL), the pH value of themixture was acidified to 5 by adding 1M aqueous HCl solution. Theprecipitate was filtered to give the desired product (1.2 g, 44%) as anorange solid.

LC-MS: (M+H)⁺ 300.1

Step C:(2-(6-Aminopyridin-3-yl)-8-chloroquinolin-4-yl)(morpholino)methanone(18)

A mixture of 2-(6-aminopyridin-3-yl)-8-chloroquinoline-4-carboxylic acid(17, step B) (300 mg, 1 mmol), morpholine (131 mg, 1.5 mmol), HOBt (270mg, 2 mmol), EDCI (382 mg, 2 mmol) and DIPEA (387 mg, 3 mmol) in DCM (15mL) was stirred at room temperature for 16 h. Water (50 mL) was added tothe reaction mixture and extracted with DCM (30 mL×3). The combinedorganic layers were concentrated and purified by silica gel columnchromatography with ethyl acetate to give the product (200 mg, 54%) as awhite solid.

LC-MS: (M+H)⁺ 369.1

Step D:N-(5-(8-Chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)pyridin-2-yl)acetamide

(2-(6-aminopyridin-3-yl)-8-chloroquinolin-4-yl)(morpholino)methanone(18, step C) (120 mg, 0.32 mmol) was dissolved in acetic anhydride (4mL) at 0° C. The resulting mixture was stirred at room temperature for 2h. Solvent was concentrated, the pH of the residue was adjusted to 7-8by adding saturated NaHCO₃ solution, and the resulting mixture wasextracted with DCM (20 mL×3). The combined organic layers wereconcentrated and purified by silica gel column chromatography with ethylacetate to give the product (60 mg, 45%) as white solid.

LC-MS: (M+H)⁺411.1

¹H NMR (400 MHz, CDCl₃) δ 9.16 (d, J=2.0 Hz, 1H), 8.60 (dd, J=8.7, 2.2Hz, 1H), 8.39 (d, J=8.7 Hz, 1H), 8.23 (s, 1H), 7.91 (dd, J=7.5, 1.1 Hz,1H), 7.84 (s, 1H), 7.75 (dd, J=8.3, 1.1 Hz, 1H), 7.56-7.48 (m, 1H),4.11-4.01 (m, 1H), 3.89 (m, 3H), 3.55 (m, 2H), 3.22 (m, 2H), 2.28 (s,3H).

Example 9 (Table 2, Compound 103)N-(6-(8-Chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)pyridin-3-yl)acetamide

Step A: 5-Nitropicolinonitrile (20)

A mixture of 2-bromo-5-nitropyridine (19) (10 g, 50 mmol) and CuCN (8.9g, 100 mmol) in DMF (25 mL) was stirred at 100° C. for 2 h. The reactionmixture was then cooled to room temperature and diluted with DCM (200mL). Solid was filtered; the filtrated was then concentrated andpurified by silica gel column chromatography with petroleum ether/ethylacetate (3:1) to give the product (3 g, 40%) as a yellow solid.

LC-MS: (M+H)⁺150.0

Step B: 5-Aminopicolinonitrile (21)

A mixture of 5-nitropicolinonitrile (20, step A) (3 g, 20 mmol), Zn (6.5g, 100 mmol) and NH₄Cl (10 g, 185 mmol) in EtOH (40 mL) was stirred forat room temperature for 2 h. The reaction was diluted with DCM (150 mL)and filtered; filtrate was concentrated and purified by silica gelcolumn chromatography with petroleum ether/ethyl acetate (3:1) to givethe product (1 g, 42%) as a yellow solid.

LC-MS: (M+H)⁺120.0

Step C: 1-(5-Aminopyridin-2-yl)ethanone (22)

To a solution of 5-aminopicolinonitrile (21, step B) (500 mg, 4.2 mmol)in THF (10 mL) was added CH₃MgCl at −78° C., the reaction mixture wasstirred for 4 h at room temperature, LCMS showed the reaction wascompleted. Water (50 mL) was added to quench the reaction and extractedwith ethyl acetate (50 mL×3). The combined organic layers wereconcentrated and purified by silica gel column chromatography withpetroleum ether/ethyl acetate (2:1) to give the product (300 mg, 53%) asa yellow solid.

LC-MS: (M+H)⁺ 137.1

Step D: 2-(5-Aminopyridin-2-yl)-8-chloroquinoline-4-carboxylic acid (23)

A solution of 1-(5-aminopyridin-2-yl)ethanone (22, step C) (1.5 g, 11.0mmol) in ethanol (10 mL) was added slowly to a solution of7-chloroindoline-2,3-dione (4) (1.66 g, 9.17 mmol) in 6M aqueous KOH (10mL) at 100° C. The reaction was monitored by LCMS until the staringmaterial consumed. Then the reaction mixture was concentrated to removeethanol, the residue was diluted with water (10 mL), the pH value of themixture was acidified to 5 by adding 1M aqueous HCl solution. Theprecipitate was filtered to give the desired product (1.2 g, 44%) as anorange solid. LC-MS: (M+H)⁺300.1

Step E:(2-(5-Aminopyridin-2-yl)-8-chloroquinolin-4-yl)(morpholino)methanone(24)

A mixture of 2-(5-aminopyridin-2-yl)-8-chloroquinoline-4-carboxylic acid(23, step D) (300 mg, 1 mmol), morpholine (131 mg, 1.5 mmol), HOBt (270mg, 2 mmol), EDCI (382 mg, 2 mmol) and DIPEA (387 mg, 3 mmol) in DCM (15mL) was stirred at room temperature for 16 h. Water (50 mL) was added tothe reaction mixture and extracted with DCM (30 mL×3). The combinedorganic layers were concentrated and purified by silica gel columnchromatography with ethyl acetate to give the product (200 mg, 54%) as awhite solid.

LC-MS: (M+H)⁺ 369.1

Step F:N-(6-(8-Chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)pyridin-3-yl)acetamide

(2-(5-aminopyridin-2-yl)-8-chloroquinolin-4-yl)(morpholino)methanone(24, step E) (116 mg, 0.32 mmol) was dissolved in acetic anhydride (3mL) at 0° C. The reaction mixture was stirred at room temperature for 2h. Solvent was concentrated, the pH of the residue was adjusted to 7-8by adding saturated NaHCO₃ solution, and the resulting mixture wasextracted with ethyl acetate (30 mL×3). The combined organic layers wereconcentrated and purified by silica gel column chromatography with ethylacetate to give the product (80 mg, 60%) as white solid.

LC-MS: (M+H)⁺411.1

¹H NMR (400 MHz, CDCl₃) δ 8.67 (dd, J=13.9, 5.0 Hz, 2H), 8.51 (s, 1H),8.18 (d, J=8.0 Hz, 1H), 7.98 (s, 1H), 7.89 (d, J=7.2 Hz, 1H), 7.75 (d,J=8.0 Hz, 1H), 7.50 (t, J=7.9 Hz, 1H), 4.04 (m, 1H), 3.97-3.81 (m, 3H),3.58 (m, 2H), 3.26 (m, 2H), 2.18 (s, 3H).

Example 10 (Table 2, Compound 104)N-(4-(6-Chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)phenyl)acetamide

Step A: 2-(4-Aminophenyl)-6-chloroquinoline-4-carboxylic acid (25)

A solution of 1-(4-aminophenyl)ethanone (2.74 g, 20.25 mmol) in ethanol(20 mL) was added slowly to a solution of 5-chloroindoline-2,3-dione (9)(2.4 g, 13.5 mmol) in 6M aqueous KOH (20 mL) at 100° C. The reaction wasmonitored by LCMS until the staring material consumed. Then the reactionmixture was concentrated to remove ethanol, the residue was diluted withwater (10 mL), the pH value of the mixture was acidified to 5 by adding1M aqueous HCl solution. The precipitate was filtered to give thedesired product (1.8 g, 45%) as an orange solid. LC-MS: (M+H)⁺ 299.1

Step B: 2-(4-Acetamidophenyl)-6-chloroquinoline-4-carboxylic acid (26)

To a solution of 2-(4-aminophenyl)-6-chloroquinoline-4-carboxylic acid(25, step A) (1.1 g, 3.79 mmol) in DCM (20 mL) was added aceticanhydride (773 mg, 7.6 mmol), Et₃N (1.15 g, 11.37 mmol) at 0° C. Themixture was stirred at room temperature for 2 h. The reaction mixturewas quenched with water (50 ml), extracted with EA (50 mL×3). Thecombined organic layers were concentrated and purified by silica gelcolumn chromatography with ethyl acetate to give the product (830 mg,64%) as a light yellow solid.

LC-MS: (M+H)⁺ 341.1

Step C:N-(4-(6-Chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)phenyl)acetamide

A mixture of 2-(4-acetamidophenyl)-6-chloroquinoline-4-carboxylic acid(200 mg, 0.58 mmol), morpholine (77 mg, 0.87 mmol), HOBt (157 mg, 1.16mmol), EDCI (221 mg, 1.16 mmol) and DIPEA (225 mg, 1.74 mmol) in DCM (15mL) was stirred at room temperature for 16 h. Water (50 mL) was added tothe reaction mixture and extracted with DCM (50 mL×3). The combinedorganic layers were concentrated and purified by silica gel columnchromatography with ethyl acetate to give the product (100 mg, 41%) as awhite solid.

LC-MS: (M+H)⁺410.1

¹H NMR (400 MHz, CDCl₃) δ 8.14 (t, J=9.9 Hz, 3H), 7.81-7.75 (m, 2H),7.74-7.63 (m, 3H), 7.42 (s, 1H), 4.04 (m, 1H), 3.89 (s, 3H), 3.68-3.50(m, 2H), 3.26 (m, 2H), 2.22 (s, 3H).

Example 11 (Table 2, Compound 105)N-(5-(6-Chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)pyridin-2-yl)acetamide

Step A: 2-(6-Aminopyridin-3-yl)-6-chloroquinoline-4-carboxylic acid (27)

A solution of 1-(6-aminopyridin-3-yl)ethanone 16, example 8, step A)(1.5 g, 11.0 mmol) in ethanol (10 mL) was added slowly to a solution of5-chloroindoline-2,3-dione (9) (1.66 g, 9.17 mmol) in 6M aqueous KOH (10mL) at 100° C. The reaction was monitored by LCMS until the staringmaterial consumed. Then the reaction mixture was concentrated to removeethanol, the residue was diluted with water (10 mL), the pH value of themixture was acidified to 5 by adding 1M aqueous HCl solution. Theprecipitate was filtered to give the desired product (1.2 g, 44%) as anorange solid.

LC-MS: (M+H)⁺ 300.1

Step B:(2-(6-Aminopyridin-3-yl)-6-chloroquinolin-4-yl)(morpholino)methanone(28)

A mixture of 2-(6-aminopyridin-3-yl)-6-chloroquinoline-4-carboxylic acid(27, step A) (300 mg, 1 mmol), morpholine (131 mg, 1.5 mmol), HOBt (270mg, 2 mmol), EDCI (382 mg, 2 mmol) and DIPEA (387 mg, 3 mmol) in DCM (15mL) was stirred at room temperature for 16 h. Water (50 mL) was added tothe reaction mixture and extracted with DCM (30 mL×3). The combinedorganic layers were concentrated and purified by silica gel columnchromatography with ethyl acetate to give the product (200 mg, 54%) as awhite solid.

LC-MS: (M+H)⁺ 369.1

Step C:N-(5-(6-Chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)pyridin-2-yl)acetamide

(2-(6-aminopyridin-3-yl)-6-chloroquinolin-4-yl)(morpholino)methanone(232 mg, 0.63 mmol) was dissolved in acetic anhydride (4 mL) at 0° C.The reaction mixture was stirred at room temperature for 2 h. Solventwas concentrated, the pH of the residue was adjusted to 7-8 by addingsaturated NaHCO₃ solution, and the resulting mixture was extracted withDCM (30 mL×3). The combined organic layers were concentrated andpurified by silica gel column chromatography with ethyl acetate to givethe product (100 mg, 39%) as a white solid.

LC-MS: (M+H)⁺411.1

¹H NMR (400 MHz, CDCl₃) δ 9.05 (d, J=1.8 Hz, 1H), 8.51 (dd, J=8.7, 2.0Hz, 1H), 8.38 (d, J=8.5 Hz, 1H), 8.29 (s, 1H), 8.13 (d, J=9.0 Hz, 1H),7.83-7.76 (m, 2H), 7.73 (dd, J=9.0, 2.3 Hz, 1H), 4.06 (m, 1H), 3.90 (m,3H), 3.59 (m, 2H), 3.26 (d, J=4.0 Hz, 2H), 2.27 (s, 3H).

Example 12 (Table 2, Compound 106)N-(6-(6-Chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)pyridin-3-yl)acetamide

Step A: 2-(5-Aminopyridin-2-yl)-6-chloroquinoline-4-carboxylic acid (29)

A solution of 1-(5-aminopyridin-2-yl)ethanone (22, Example 9, step C)(1.5 g, 11.0 mmol) in ethanol (10 mL) was added slowly to a solution of5-chloroindoline-2,3-dione (9) (1.66 g, 9.17 mmol) in 6M aqueous KOH (10mL) at 100° C. The reaction was monitored by LCMS until the staringmaterial consumed. Then the reaction mixture was concentrated to removeethanol, the residue was diluted with water (10 mL), the pH value of themixture was acidified to 5 by adding 1M aqueous HCl solution. Theprecipitate was filtered to give the desired product (1 g, 36%) as anorange solid.

LC-MS: (M+H)⁺ 300.1

Step B:(2-(5-Aminopyridin-2-yl)-6-chloroquinolin-4-yl)(morpholino)methanone(30)

A mixture 2-(5-aminopyridin-2-yl)-6-chloroquinoline-4-carboxylic acid(29, step A) (300 mg, 1 mmol), morpholine (131 mg, 1.5 mmol), HOBt (270mg, 2 mmol), EDCI (382 mg, 2 mmol) and DIPEA (387 mg, 3 mmol) in DCM (15mL) was stirred at room temperature for 16 h. Water (50 mL) was added tothe reaction mixture and extracted with DCM (30 mL×3). The combinedorganic layers were concentrated and purified by silica gel columnchromatography with ethyl acetate to give the product (180 mg, 48%) as awhite solid.

LC-MS: (M+H)⁺ 369.1

Step C:N-(6-(6-Chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)pyridin-3-yl)acetamide

(2-(5-aminopyridin-2-yl)-6-chloroquinolin-4-yl)(morpholino)methanone(30, step B) (116 mg, 0.32 mmol) was dissolved in acetic anhydride (3mL) at 0° C. The reaction mixture was stirred at room temperature for 2h. Solvent was concentrated, the pH of the residue was adjusted to 7-8by adding saturated NaHCO₃ solution, and the resulting mixture wasextracted with ethyl acetate (30 mL×3). The combined organic layers wereconcentrated and purified by silica gel column chromatography with ethylacetate to give the product (30 mg, 23%) as a white solid.

LC-MS: (M+H)⁺411.1

¹H NMR (400 MHz, CDCl₃) δ 8.60 (s, 1H), 8.49 (d, J=8.7 Hz, 1H), 8.42 (s,1H), 8.23 (d, J=7.7 Hz, 1H), 8.11 (d, J=9.0 Hz, 2H), 7.80 (d, J=2.2 Hz,1H), 7.71 (dd, J=9.0, 2.3 Hz, 1H), 4.05 (m, 1H), 3.90 (m, 3H), 3.61 (d,J=35.4 Hz, 2H), 3.31 (d, J=25.1 Hz, 2H), 2.20 (s, 3H).

Example 13 (Table 2, Compound 107)N-(4-(4-Morpholinoquinolin-2-yl)phenyl)acetamide

Step A: tert-Butyl 4-(4-chloroquinolin-2-yl)phenylcarbamate (31)

A mixture of 2,4-dichloroquinoline (2.0 g, 10 mmol), tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (3.8 g,12 mmol), Cs₂CO₃ (6.5 g, 20 mmol) and Pd(PP₃)₄ (600 mg, 1.0 mmol) in DMF(25 mL) was stirred in a sealed tube at 100° C. for 30 min. The reactionwas cooled to room temperature; Water (200 mL) was added to the reactionmixture and extracted with ethyl acetate (50 mL×3). The combined organiclayers were concentrated and purified by silica gel columnchromatography with petroleum ether/ethyl acetate (3:1) to give theproduct (1 g, 28%) as a yellow solid.

LC-MS: (M+H)⁺ 355.1

Step B: tert-Butyl 4-(4-morpholinoquinolin-2-yl)phenylcarbamate (32)

A mixture of tert-butyl 4-(4-chloroquinolin-2-yl)phenylcarbamate (31,step A) (1 g, 2.8 mmol) and morpholine (0.5 g, 5.6 mmol) in DMF (10 mL)was added DIPEA (1 g, 8.4 mmol) was stirred at 120° C. for 2 h. thereaction mixture was cooled to room temperature; Water (50 mL) was addedand extracted with ethyl acetate (50 mL×3). The combined organic layerswere concentrated an purified by silica gel column chromatography withpetroleum ether/ethyl acetate (1:1) to give the product (500 mg, 44%) asa yellow solid.

LC-MS: (M+H)⁺ 406.2

Step C: 4-(4-Morpholinoquinolin-2-yl)benzenamine (33)

tert-butyl 4-(4-morpholinoquinolin-2-yl)phenylcarbamate (32, step B)(500 mg, 1.23 mmol) in 4M HCl in Dioxane solution (10 mL) was stirred atroom temperature for 2 h. the reaction mixture was concentrated to givethe crude product (350 mg) which was used into next step withoutpurification.

LC-MS: (M+H)⁺ 306.2

Step D: N-(4-(4-Morpholinoquinolin-2-yl)phenyl)acetamide

To a solution of 4-(4-morpholinoquinolin-2-yl)benzenamine (33, step C)(150 mg, 0.49 mmol) in DCM (20 mL) was added acetic anhydride (150 mg,1.47 mmol), Et₃N (198 mg, 1.96 mmol) at 0° C. The mixture was stirred atroom temperature for 2 h. The resulting mixture was quenched with H₂O(50 ml), extracted with DCM (30 mL×2). The combined organic layersconcentrated and purified by silica gel column chromatography with ethylacetate to give the product (60 mg, 35%) as a white solid.

LC-MS: (M+H)⁺ 348.2

¹H NMR (400 MHz, CDCl₃) δ 8.11 (t, J=7.9 Hz, 3H), 8.02 (d, J=7.7 Hz,1H), 7.67 (dd, J=7.6, 4.5 Hz, 3H), 7.47 (t, J=7.6 Hz, 1H), 7.30 (d,J=8.9 Hz, 2H), 4.06-3.97 (m, 4H), 3.37-3.26 (m, 4H), 2.22 (s, 3H).

Example 14 (Table 2, Compound 108)N-(4-(4-(Morpholinomethyl)quinolin-2-yl)phenyl)acetamide

Step A: (2-(4-Aminophenyl)quinolin-4-yl)(morpholino)methanone (34)

A mixture of 2-(4-aminophenyl)quinoline-4-carboxylic acid (2, Example 1,step A) (1.0 g, 3.8 mmol), morpholine (496 mg, 5.7 mmol), HOBt (1.03 g,7.6 mmol), EDCI (1.45 g, 7.6 mmol) and DIPEA (1.47 g, 11.4 mmol) in DCM(30 mL) was stirred at room temperature for 16 h. Water (50 mL) wasadded to the reaction mixture and extracted with EA (50 mL×3). Thecombined organic layers were concentrated and purified by silica gelcolumn chromatography with ethyl acetate to give the product (800 mg,63%) as a white solid.

LC-MS: (M+H)⁺ 334.2

Step B: 4-(4-(Morpholinomethyl)quinolin-2-yl)benzenamine (35)

To a solution of (2-(4-aminophenyl)quinolin-4-yl)(morpholino)methanone(34, step A) (500 mg, 1.5 mmol) in THF (15 mL) was added BH3/THF (4.5ml, 4.5 mmol) at 0° C., and the reaction was stirred at room temperaturefor 1 h. Water was added to quench the reaction, extracted with ethylacetate (30 mL×3). The combined organic layers were concentrated andpurified by silica gel column chromatography with DCM/methanol (15:1) togive the product (400 mg, 8.3%) as a yellow solid.

LC-MS: (M+H)⁺ 320.2

Step C: N-(4-(4-(Morpholinomethyl)quinolin-2-yl)phenyl)acetamide

To a solution of 4-(4-(morpholinomethyl)quinolin-2-yl)benzenamine (200mg, 0.63 mmol) in DCM (20 mL) was added acetic anhydride (96 mg, 0.94mmol) and Et₃N (127 mg, 1.26 mmol) at 0° C. The mixture was stirred atroom temperature for 2 h. The resulting mixture was quenched with water(50 ml), extracted with EA (30 mL×3). The combined organic layers wereconcentrated and purified by silica gel column chromatography withDCM/methanol (15:1) to give the product (100 mg, 44%) as a white solid.

LC-MS: (M+H)⁺362.2

¹H NMR (400 MHz, CDCl₃) δ 8.23 (d, J=8.2 Hz, 1H), 8.17 (d, J=8.6 Hz,3H), 7.90 (s, 1H), 7.75-7.66 (m, 3H), 7.54 (dd, J=11.2, 4.0 Hz, 1H),7.34 (s, 1H), 3.98 (s, 2H), 3.82-3.67 (m, 4H), 2.58 (m, 4H), 2.23 (s,3H).

Example 15 (Table 2, Compound 109)N-(6-(4-(Morpholinomethyl)quinolin-2-yl)pyridin-3-yl)acetamide

Step A: 2-(5-Aminopyridin-2-yl)quinoline-4-carboxylic acid (36)

A solution of 1-(5-aminopyridin-2-yl)ethanone (22, Example 9 step C)(478 mg, 3.51 mmol) in ethanol (5 mL) was added slowly to a solution ofindoline-2,3-dione (1)(400 mg, 2.7 mmol) in 6M aqueous KOH (5 mL) at100° C. The reaction was monitored by LCMS until the staring materialconsumed. Then the reaction mixture was concentrated to remove ethanol,the residue was diluted with water (20 mL), the pH value of the mixturewas acidified to 5 by adding 1M aqueous HCl solution. The precipitatewas filtered to give the desired product (400 mg, 56%) as an orangesolid.

LC-MS: (M+H)⁺ 266.2

Step B: (2-(5-Aminopyridin-2-yl)quinolin-4-yl)(morpholino)methanone (37)

A mixture of 2-(5-aminopyridin-2-yl)quinoline-4-carboxylic acid (36,step A) (0.4 g, 1.5 mmol), morpholine (263 mg, 3.0 mmol), HOBt (405 mg,3.0 mmol), EDCI (573 mg, 3.0 mmol) and DIPEA (581 mg, 4.5 mmol) in DCM(20 mL) was stirred at room temperature for 16 h. Water (50 mL) wasadded to the reaction mixture and extracted with EA (30 mL×3). Thecombined organic layers were concentrated and purified by silica gelcolumn chromatography with ethyl acetate to give the product (230 mg,46%) as a white solid.

LC-MS: (M+H)⁺ 333.2

Step C: 6-(4-(Morpholinomethyl)quinolin-2-yl)pyridin-3-amine (38)

To a solution of(2-(5-aminopyridin-2-yl)quinolin-4-yl)(morpholino)methanone (37, step B)(230 mg, 0.69 mmol) in THF (15 mL) was added BH₃/THF (3.5 ml, 3.5 mmol)at 0° C., the reaction was stirred at room temperature for 2 h. Waterwas added to quench the reaction, extracted with ethyl acetate (20mL×3). The combined organic layers were concentrated and purified bysilica gel column chromatography with DCM/methanol (15:1) to give theproduct (175 mg, 79%) as a little yellow solid.

LC-MS: (M+H)⁺ 321.2

Step D: N-(6-(4-(Morpholinomethyl)quinolin-2-yl)pyridin-3-yl)acetamide

6-(4-(morpholinomethyl)quinolin-2-yl)pyridin-3-amine (38, step C) (175mg, 0.55 mmol) was dissolved in acetic anhydride (5 mL) at 0° C. Thereaction mixture was stirred at room temperature for 2 h. Solvent wasconcentrated, the pH of the residue was adjusted to 7-8 by addingsaturated NaHCO₃ solution, and the resulting mixture was extracted withDCM (30 mL×3). The combined organic layers were concentrated andpurified by prep-HPLC to give the product (60 mg, 30%) as an off whitesolid.

LC-MS: (M+H)⁺ 363.2

¹H NMR (400 MHz, MeOD) δ 8.91 (d, J=2.2 Hz, 1H), 8.52 (d, J=8.7 Hz, 1H),8.45 (s, 1H), 8.40-8.32 (m, 1H), 8.27 (dd, J=8.7, 2.5 Hz, 1H), 8.15 (d,J=8.0 Hz, 1H), 7.78 (m, 1H), 7.63 (m, 1H), 4.07 (s, 2H), 3.77-3.68 (m,4H), 2.64-2.53 (m, 4H), 2.23 (s, 3H).

Example 16 (Table 2, Compound 110)N-(4-(8-Chloro-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide

Step A: (2-(4-Aminophenyl)-8-chloroquinolin-4-yl)(morpholino)methanone(39)

A mixture of 2-(4-aminophenyl)-8-chloroquinoline-4-carboxylic acid (13,example 7 step A) (0.8 g, 2.68 mmol), morpholine (467 mg, 5.36 mmol),HOBt (723 mg, 5.36 mmol), EDCI (1.02 g, 5.36 mmol) and DIPEA (1.04 g,8.04 mmol) in DCM (30 mL) was stirred at room temperature for 16 h.Water (50 mL) was added to the reaction mixture and extracted with EA(50 mL×3). The combined organic layers were concentrated and purified bysilica gel column chromatography with ethyl acetate to give the product(950 mg, 97%) as a white solid.

LC-MS: (M+H)⁺ 366.2

Step B: 4-(8-Chloro-4-(morpholinomethyl)quinolin-2-yl)benzenamine (40)

To a solution of(2-(4-aminophenyl)-8-chloroquinolin-4-yl)(morpholino)methanone (39, stepA) (300 mg, 0.82 mmol) in THF (15 mL) was added BH3/THF (4.5 ml, 4.5mmol) at 0° C., and the reaction was stirred at room temperature for 2h. Water was added to quench the reaction, extracted with ethyl acetate(30 mL×3). The combined organic layers were concentrated and purified bysilica gel column chromatography with DCM/methanol (15:1) to give theproduct (230 mg, 79%) as a yellow solid.

LC-MS: (M+H)⁺ 354.2

Step C:N-(4-(8-Chloro-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide

4-(8-Chloro-4-(morpholinomethyl)quinolin-2-yl)benzenamine (230 mg, 0.65mmol) was dissolved in acetic anhydride (5 mL) at 0° C. The reactionmixture was stirred at room temperature for 2 h. Solvent wasconcentrated, the pH of the residue was adjusted to 7-8 by addingsaturated NaHCO₃ solution, and the resulting mixture was extracted withDCM (30 mL×3). The combined organic layers were concentrated andpurified by prep-HPLC to give the product (45 mg, 18%) as a littleyellow solid.

LC-MS: (M+H)⁺ 396.2

¹H NMR (400 MHz, CDCl₃) δ 8.29 (d, J=5.1 Hz, 2H), 8.15 (s, 1H), 7.96 (s,1H), 7.84 (d, J=7.1 Hz, 1H), 7.69 (d, J=8.5 Hz, 2H), 7.43 (t, J=7.8 Hz,1H), 7.31 (s, 1H), 3.96 (s, 2H), 3.8-3.66 (m, 4H), 2.68-2.46 (s, 4H),2.23 (s, 3H).

Example 17 (Table 2, Compound 111)N-(6-(8-Chloro-4-(morpholinomethyl)quinolin-2-yl)pyridin-3-yl)acetamide

Step A: 6-(8-Chloro-4-(morpholinomethyl)quinolin-2-yl)pyridin-3-amine(41)

To a solution of(2-(5-aminopyridin-2-yl)-8-chloroquinolin-4-yl)(morpholino)methanone(24, example 9 step E) (400 mg, 1.1 mmol) in THF (15 mL) was addedBH3/THF (6.6 ml, 6.6 mmol) at 0° C., and the reaction was stirred atroom temperature for 2 h. Water was added to quench the reaction,extracted with ethyl acetate (20 mL×3). The combined organic layers wereconcentrated and purified by silica gel column chromatography withDCM/methanol (15:1) to give the product (250 mg, 64%) as a white solid.

LC-MS: (M+H)⁺ 355.1

Step B:N-(6-(8-Chloro-4-(morpholinomethyl)quinolin-2-yl)pyridin-3-yl)acetamide

6-(8-chloro-4-(morpholinomethyl)quinolin-2-yl)pyridin-3-amine (250 mg,0.70 mmol) was dissolved in acetic anhydride (5 mL) at 0° C. Thereaction mixture was stirred at room temperature for 2 h. Solvent wasconcentrated, the pH of the residue was adjusted to 7-8 by addingsaturated NaHCO₃ solution, and the resulting mixture was extracted withDCM (30 mL×3). The combined organic layers were concentrated andpurified by prep-HPLC to give the product (32 mg, 12%) as a white solid.

LC-MS: (M+H)⁺ 397.2

¹H NMR (400 MHz, DMSO) δ 10.43 (s, 1H), 8.94 (d, J=2.0 Hz, 1H), 8.63 (d,J=8.6 Hz, 1H), 8.57 (s, 1H), 8.32 (d, J=8.4 Hz, 1H), 8.26 (dd, J=8.7,2.2 Hz, 1H), 7.98 (d, J=7.4 Hz, 1H), 7.60 (t, J=8.0 Hz, 1H), 4.02 (s,2H), 3.63-3.54 (m, 4H), 3.33 (m, 4H), 2.14 (s, 3H).

Example 18 (Table 2, Compound 112)N-(4-(4-(1-Morpholinoethyl)quinolin-2-yl)phenyl)acetamide

Step A: 2-(4-Acetamidophenyl)-N-methoxy-N-methylquinoline-4-carboxamide(42)

A mixture of 2-(4-acetamidophenyl)quinoline-4-carboxylic acid (3,example 1, step B) (1.1 g, 3.6 mmol), N,O-dimethylhydroxylaminehydrochloride (526 mg, 5.4 mmol), HOBt (972 mg, 7.2 mmol), EDCI (1.4 g,7.2 mmol) and DIPEA (1.4 g, 10.8 mmol) in DCM (25 mL) was stirred atroom temperature for 16 h. Water (50 mL) was added to the reactionmixture and extracted with ethyl acetate (50 mL×3). The combined organiclayers were concentrated and purified by silica gel columnchromatography with ethyl acetate to give the product (1.2 g, 95%) as awhite solid.

LC-MS: (M+H)⁺ 350.1

Step B: N-(4-(4-Acetylquinolin-2-yl)phenyl)acetamide (43)

To a solution of2-(4-acetamidophenyl)-N-methoxy-N-methylquinoline-4-carboxamide (42,step A) (1.1 g, 3.15 mmol) in THF (20 mL) was added 1N CH₃MgBr (2.2 mL,2.2 mmol) at −78° C., the reaction mixture was stirred for 3 h at roomtemperature, LCMS showed the reaction was completed. Water (50 mL) wasadded to quench the reaction and extracted with ethyl acetate (50 mL×3).The combined organic layers were concentrated and purified by silica gelcolumn chromatography with ethyl acetate to give the product (780 mg,81%) as a white solid.

LC-MS: (M+H)⁺ 305.1

Step C: N-(4-(4-(1-Morpholinoethyl)quinolin-2-yl)phenyl)acetamide

A mixture of N-(4-(4-acetylquinolin-2-yl)phenyl)acetamide (43, step B)(300 mg, 0.99 mmol), morpholine (129 mg, 1.48 mmol), NaBH(OAc)₃ (420 mg,1.98 mmol) and AcOH (10 mg, 0.1 mmol) in DCM (25 mL) was stirred at roomtemperature for 24 h. Water (50 mL) was added to the reaction mixtureand extracted with ethyl acetate (50 mL×3). The combined organic layerswere concentrated and purified by prep-HPLC the product (50 mg, 14%) asa yellow solid.

LC-MS: (M+H)⁺ 376.2

¹H NMR (400 MHz, CDCl₃) δ 8.32 (d, J=8.4 Hz, 1H), 8.24-8.06 (m, 4H),8.08 (s, 1H), 7.77-7.65 (m, 3H), 7.55 (t, J=7.4 Hz, 1H), 7.43 (s, 1H),4.21 (s, 1H), 3.87-3.73 (m, 4H), 2.75 (s, 2H), 2.57 (s, 2H), 2.23 (s,3H), 1.58 (d, J=6.3 Hz, 3H).

Example 19 (Table 2, Compound 113)

Step A: 2-(4-(2,2,2-trifluoroacetamido)phenyl)quinoline-4-carboxylicacid (44)

To a solution of 2-(4-aminophenyl)quinoline-4-carboxylic acid (Compound2, Example 1) (2.0 g, 7.57 mmol) in DCM (20 mL) was added2,2,2-trifluoroacetic anhydride (2.38 g, 11.36 mmol) and Et₃N (1.53 g,15.14 mmol) at 0° C. The mixture was stirred at room temperature for 2h. The resulting solution was quenched with water (100 ml) and extractedwith DCM (50 mL×2). The combined organic layers were concentrated andthe crude was without purification to give the product (2.5 g, 91%) as alight yellow solid.

LC-MS: (M+H)⁺ 361.1

Step B: 2-(4-(2,2,2-trifluoroacetamido)phenyl)quinoline-4-carbonylchloride (45)

To a solution of2-(4-(2,2,2-trifluoroacetamido)phenyl)quinoline-4-carboxylic acid (44,step A) (1.2 g, 3.3 mmol) in DCM (20 mL) was added oxalyl chloride (0.42ml, 4.95 mmol) and 1 drop of DMF at 0° C. The mixture was stirred atroom temperature for 2 h. The resulting solution was concentrated togive the crude product (1 g) as light yellow oil which was used in thenext step without purification.

LC-MS: (M+H)⁺ 379.0

Step C:N-(4-(4-(2-diazoacetyl)quinolin-2-yl)phenyl)-2,2,2-trifluoroacetamide(46)

To a solution of2-(4-(2,2,2-trifluoroacetamido)phenyl)quinoline-4-carbonyl chloride (45,step B)(1 g, 2.65 mmol) in CH₃CN (20 mL) was added TMSCH₂N₂ (605 mg, 5.3mmol) at rt and the mixture was stirred at room temperature for 2 h. Theresulting solution was concentrated to give the crude product (1 g) aslight yellow oil which was used in the next step without purification.

LC-MS: (M+H)⁺ 385.1

Step D:2,2,2-trifluoro-N-(4-(4-(2-morpholino-2-oxoethyl)quinolin-2-yl)phenyl)acetamide(47)

A solution ofN-(4-(4-(2-diazoacetyl)quinolin-2-yl)phenyl)-2,2,2-trifluoroacetamide(46, step C) (1 g, 2.6 mmol) in morpholine (10 mL) was stirred at 80° C.under MW for 1 h. The resulting solution was washed with H₂O (50 ml),extracted with EA (50 mL×3). The combined organic layers wereconcentrated to give the crude product which was purified by silica gelcolumn chromatography with PE/EA (1/1) to give the product (400 mg, 35%)as a light yellow solid.

LC-MS: (M+H)⁺ 444.2

Step E: 2-(2-(4-aminophenyl)quinolin-4-yl)-1-morpholinoethanone (48)

To a solution of2,2,2-trifluoro-N-(4-(4-(2-morpholino-2-oxoethyl)quinolin-2-yl)phenyl)acetamide(47, step D) (400 mg, 0.90 mmol) in EtOH (10 mL) was added K₂CO₃ (248mg, 1.8 mmol) at 70° C. and stirred overnight. The resulting solutionwas diluted with H₂O (50 ml), extracted with EA (50 mL×3). The combinedorganic layers were washed with brine, dried over Na₂SO₄, concentrated.The crude product was purified by silica gel column chromatography withEA to give the product (300 mg, 95%) as a light yellow solid.

LC-MS: (M+H)⁺ 348.2

¹H NMR (400 MHz, DMSO) δ 8.15 (s, 1H), 8.01-7.89 (m, 4H), 7.82 (s, 1H),7.70-7.64 (m, 1H), 7.50-7.44 (m, 1H), 6.73-6.65 (m, 2H), 5.56 (s, 2H),4.25 (s, 2H), 3.70-3.56 (m, 6H), 3.52-3.45 (m, 2H).

Step F: 4-(4-(2-morpholinoethyl)quinolin-2-yl)benzenamine (49)

To a solution of2,2,2-trifluoro-N-(4-(4-(2-morpholino-2-oxoethyl)quinolin-2-yl)phenyl)acetamide(48, step E) (200 mg, 0.45 mmol) in THF (15 mL) was added BH₃/THF (4.5ml, 4.5 mmol) at 0° C., and the reaction was stirred at 0° C. for 2 h.Methanol (10 mL) was added and the resulting mixture was stirred at rtovernight. Solvent was concentrated to give the crude product which waspurified by silica gel column chromatography with DCM/methanol (15/1) togive the product (120 mg, 80%) as a light yellow solid.

LC-MS: (M+H)⁺ 334.2

¹H NMR (400 MHz, MeOD) δ 8.16 (d, J=8.1 Hz, 1H), 8.08 (d, J=8.2 Hz, 1H),7.98-7.90 (m, 2H), 7.86 (s, 1H), 7.80-7.73 (m, 1H), 7.67-7.55 (m, 1H),6.92-6.81 (m, 2H), 3.88-3.75 (m, 4H), 3.48-3.39 (m, 2H), 3.02-2.91 (m,2H), 2.87-2.71 (m, 4H).

Step G: N-(4-(4-(2-morpholinoethyl)quinolin-2-yl)phenyl)acetamide(Compound 113)

4-(4-(2-morpholinoethyl)quinolin-2-yl)benzenamine (49, Step F) (70 mg,0.21 mmol) was dissolved in acetic anhydride (5 mL) at 0° C. Thereaction mixture was stirred at room temperature for 2 h. Solvent wasconcentrated, the pH of the residue was adjusted to 7-8 by addingsaturated NaHCO₃ solution, and the resulting mixture was extracted withDCM (30 mL×3). The combined organic layers were concentrated andpurified with prep-HPLC to give the product (40 mg, 51%) as a whitesolid (formate salt).

LC-MS: (M+H)⁺ 376.2

¹H NMR (400 MHz, DMSO) δ 10.15 (s, 1H), 8.26-8.21 (m, 2H), 8.20-8.10 (m,2H), 8.06-8.00 (m, 2H), 7.80-7.70 (m, 3H), 7.64-7.54 (m, 1H), 3.65-3.56(m, 4H), 3.35-3.26 (m, 2H), 2.75-2.65 (m, 2H), 2.54 (d, J=4.0 Hz, 4H),2.09 (s, 3H).

Example 20

N-(4-(4-(2-morpholino-2-oxoethyl)quinolin-2-yl)phenyl)acetamide

2-(2-(4-aminophenyl)quinolin-4-yl)-1-morpholinoethanone (Example 19,Step E, 48) (90 mg, 0.26 mmol) was dissolved in acetic anhydride (5 mL)at 0° C. The reaction mixture was stirred at room temperature for 2 h.The reaction was monitored by LCMS until the starting material consumed.Solvent was concentrated, the pH of the residue was adjusted to 7-8 byadding saturated NaHCO₃ solution, and the resulting mixture wasextracted with DCM (30 mL×3). The combined organic layers wereconcentrated and purified with prep-HPLC to give the product (24 mg,24%) as a white solid.

LC-MS: (M+H)⁺ 390.2

¹H NMR (400 MHz, DMSO) δ 10.16 (s, 1H), 8.20 (d, J=8.8 Hz, 2H),8.07-7.92 (m, 3H), 7.80-7.68 (m, 3H), 7.60-7.51 (m, 1H), 4.31 (s, 2H),3.70-3.55 (m, 6H), 3.53-3.44 (m, 2H), 2.09 (s, 3H).

Example 21 (Table 3, Compound 254)

Step 1 2-(4-amino-3-chlorophenyl)-7-chloroquinoline-4-carboxylic acid

A solution of 1-(4-amino-3-chlorophenyl)ethan-1-one (4.2 g, 24.9 mmol)in EtOH (20 mL) was added to a solution of 6-chloroindoline-2,3-dione (3g, 16.6 mmol) in 6 M aqueous KOH (20 mL) at 100° C. The reaction wasmonitored by LC-MS until the starting material consumed. Then thereaction mixture was concentrated to remove EtOH, then adjusted the pHto 4-5. The precipitate was filtered to give the desired product2-(4-amino-3-chlorophenyl)-7-chloroquinoline-4-carboxylic acid (4.1 g,74.5%) as red solid.

Step 2(2-(4-amino-3-chlorophenyl)-7-chloroquinolin-4-yl)(morpholino)methanone

A solution of 2-(4-amino-3-chlorophenyl)-7-chloroquinoline-4-carboxylic(product of step 1) (1 g, 3 mmol), morpholine (390 mg, 4.5 mmol), EDCI(1.15 g, 6 mmol), HOBt (810 mg, 6 mmol) and DIPEA (774 mg, 6 mmol) inTHF (20 mL) was stirred at 25° C. for 16 h. The reaction wasconcentrated to get crude product, then was purified through silicon-gelcolumn to provide the desired product(2-(4-amino-3-chlorophenyl)-7-chloroquinolin-4-yl)(morpholino)methanone(890 mg, 74%) as solid.

Step 3 2-chloro-4-(7-chloro-4-(morpholinomethyl) quinolin-2-yl)aniline

To a solution of (2-(4-amino-3-chlorophenyl)-7-chloroquinolin-4-yl)(morpholino) methanone (product of step 2) (1 g, 2.48 mmol) in THF (15mL) was added BH₃-THF (1 M, 12 mL, 12 mmol) at 0° C. The solution washeated to 35° C. for 16 h under N₂ protection. The reaction was quenchedby adding 10 mL MeOH and con. HCl (1 mL) at 0° C. The mixture was heatedto 50° C. for 0.5 h, then concentrated under vacuum to get crudeproduct. The crude product was dissolved into water (50 mL) and pH wasadjusted to round 10 by adding 1 M NaOH. The product was extracted fromwater by EA (30 mL*3), then dried over anhydrous Na₂SO₄ and concentratedto get crude desired product 2-chloro-4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl) aniline (1.05 g, crude yield 105%) as solid.

Step 4N-(2-chloro-4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide(Compound 254) (Example 21)

To a solution of2-chloro-4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)aniline (productof step 3) (100 mg, 0.25 mmol) and DIPEA (66 mg, 0.52 mmol) in THF (5mL) was added AcCl (24 mg, 0.3 mmol) at 0° C. The solution was stirredat 0° C. for 0.5 h, then quenched by adding 1 drop of water. The mixturewas concentrated and purified through prep-HPLC to provide RAGE-254 (HClsalt, 30 mg, 12.5%) as orange salt.

1H NMR (400 MHz, MeOD) δ 8.76 (s, 1H), 8.56 (d, J=8.8 Hz, 1H), 8.50 (d,J-1.6 Hz, 1H), 8.37-8.38 (m, 1H), 8.27-8.28 (m, 2H), 7.91-7.94 (m, 1H),5.12 (s, 2H), 4.03 (s, 4H), 3.53-3.55 (m, 4H), 2.29 (s, 3H). LC-MS:430.1[M+1]+rt=1.454 min

The similar synthetic route was used to the following compounds:

Example 22 (Table 3, Compound 250)

N-(2-fluoro-4-(7-fluoro-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide

The title compound was prepared according the procedure for Compound 254(Example 21) starting from reagent A (6-fluoroindoline-2,3-dione) andreagent B (1-(4-amino-3-fluoro phenyl)ethan-1-one).

¹H NMR (400 MHz, MeOD) δ 8.64 (s, 1H), 8.55 (dd, J=9.2, 5.5 Hz, 1H),8.34 (t, J=8.2 Hz, 1H), 8.12 (dd, J=12.0, 2.0 Hz, 1H), 8.03 (dd, J=8.6,1.8 Hz, 1H), 7.94 (dd, J=9.3, 1.7 Hz, 1H), 7.74-7.64 (m, 1H), 5.03 (s,2H), 3.91 (s, 4H), 3.43 (d, J=3.9 Hz, 4H), 2.15 (s, 3H). LC-MS: 398.2[M+1]⁺, rt=1.308

Example 23 (Table 3, Compound 251)

N-(2-chloro-4-(7-fluoro-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide

The title compound was prepared according the procedure for Compound 254(Example 21) starting from reagent A (6-fluoroindoline-2,3-dione) andreagent B (1-(4-amino-3-chlorophenyl)ethan-1-one).

¹H NMR (400 MHz, MeOD) δ 8.85 (s, 1H), 8.72 (dd, J=9.3, 5.4 Hz, 1H),8.47 (s, 1H), 8.27 (dd, J=18.7, 8.6 Hz, 2H), 8.10 (dd, J=9.1, 2.0 Hz,1H), 7.83 (dd, J=12.3, 5.1 Hz, 1H), 5.19 (s, 2H), 4.03 (s, 4H), 3.56 (d,J=3.9 Hz, 4H), 2.27 (s, 3H). LC-MS: 414.1[M+1]⁺, rt=1.199 min

Example 24 (Table 3, Compound 253)

N-(4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)-2-fluorophenyl)acetamide

The title compound was prepared according the procedure for Compound 254(Example 21) starting from reagent A (6-chloroindoline-2,3-dione) andreagent B (1-(4-amino-3-fluoro phenyl)ethan-1-one)

δ 1H NMR (400 MHz, MeOD) δ 8.63 (s, 1H), 8.47 (d, 1H), 8.38 (t, 1H),8.32 (d, 1H), 8.20 (dd, 1H), 8.11 (d, 1H), 7.85 (dd, 1H), 5.05 (s, 2H),4.00 (s, 4H), 3.50 (d, 4H), 2.23 (s, 3H). LC-MS: 414.2 [M+1]⁺, rt=1.394min

Example 25 (Table 3, Compound 256)

N-(2-fluoro-4-(7-methoxy-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide

The title compound was prepared according the procedure for Compound 254(Example 21) starting from reagent A (6-methoxyindoline-2,3-dione) andreagent B (1-(4-amino-3-fluorophenyl)ethan-1-one)

1H NMR (400 MHz, MeOD) δ 8.60 (s, 1H), 8.53 (dd, J=8.8, 6.0 Hz, 2H),8.20 (dd, J=11.8, 2.1 Hz, 1H), 8.12-8.05 (m, 1H), 7.76 (d, J=2.5 Hz,1H), 7.66 (dd, J=9.4, 2.5 Hz, 1H), 5.10 (s, 2H), 4.14 (s, 3H), 4.01 (s,4H), 3.58-3.40 (m, 4H), 2.28 (s, 3H). LC-MS: 410.3[M+1]+, rt=1.255 min

Example 26 (Table 3, Compound 257)

N-(2-chloro-4-(7-methoxy-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide

The title compound was prepared according the procedure for Compound 254(Example 21) starting from reagent A (6-methoxyindoline-2,3-dione) andreagent B (1-(4-amino-3-chlorophenyl)ethan-1-one)

1H NMR (400 MHz, MeOD) δ 8.56 (s, 1H), 8.47-8.56 (m, 1H), 8.43 (s, 1H),8.28-8.31 (m, 1H), 8.19-8.22 (m, 1H), 7.74 (s, 1H), 7.58-7.61 (m, 1H),4.96 (s, 2H), 4.00 (s, 3H), 3.89 (s, 4H), 3.39 (s, 4H), 2.18 (s, 3H).LC-MS: 426.2 [M+1]+, rt=1.156 min

Example 27 (Table 3, Compound 262)

N-(4-(7-ethoxy-4-(morpholinomethyl)quinolin-2-yl)-2-fluorophenyl)acetamide

In the synthesis of Compound 257 (Example 26), EtOH was used at solventin the 1^(st) step reaction. The title compound was formed as by-productand it was separated by prep-HPLC in the final step.

¹H NMR (400 MHz, MeOD) δ 8.71 (s, 1H), 8.64-8.54 (m, 2H), 8.22 (dd,J=11.8, 2.2 Hz, 1H), 8.10 (dd, J=8.7, 1.6 Hz, 1H), 7.78 (d, J=2.4 Hz,1H), 7.68 (dd, J=9.4, 2.4 Hz, 1H), 5.15 (s, 2H), 4.41 (q, J=7.0 Hz, 2H),4.04 (s, 4H), 3.54 (d, J=4.0 Hz, 4H), 2.28 (s, 3H), 1.58 (t, J=7.0 Hz,3H). LC-MS: 424.2 [M+1]+, rt=1.308 min

Example 28 (Table 3, Compound 260 and 261) Part B

To a solution of Compound 254 (Example 21)2-chloro-4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)aniline (400 mg,0.93 mmol), Zn(CN)₂ (75 mg, 0.65 mmol) and XPpos (88 mg, 0.18 mmol) inDME (10 mL) was added [(allyl)PdCl]₂ (33 mg, 0.09 mmol) at 25° C. underN₂ protection. The reaction was heated to 120° C. for 10 h. The productwas purified through prep-HPLC to get Compound 260N-(2-chloro-4-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide (Example 28a) (29.1 mg, 7.4%) andCompound 261N-(2-cyano-4-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide(Example 28b) (54 mg, 14.0%).

Compound 260 (28a)

1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 8.63 (s, 1H), 8.52-8.54 (m,1H), 8.44 (s, 1H), 8.31 (s, 1H), 8.25-8.27 (m, 1H), 8.03-8.05 (m, 1H),7.92-7.94 (m, 1H), 4.02 (s, 2H), 3.57 (s, 4H), 2.49 (s, 4H), 2.17 (s,3H). LC-MS: 421.1 [M+1]⁺, rt=1.241 min

Compound 261 (28b)

1H NMR (400 MHz, MeOD) δ 8.56 (s, 1H), 8.45-8.48 (m, 3H), 8.13 (s, 1H),7.85-7.87 (m, 1H), 7.69-7.72 (m, 1H), 3.97 (s, 2H), 3.59-3.61 (m, 4H),2.47-2.49 (m, 4H), 2.16 (s, 3H). LC-MS: 412.2[M+1]⁺, rt=1.146 min

The similar synthetic route was used to the following compounds:

Example 29 (Table 3, Compound 255)

N-(4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)-2-cyanophenyl)acetamide

The title compound was prepared according the procedure for Compound 260(Example 28) starting fromN-(4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)-2-iodophenyl)acetamide(which was prepared according the procedure for Compound 254 (Example21) starting from 6-chloroindoline-2,3-dione and1-(4-amino-3-iodophenyl)ethan-1-one) by utilizing same procedure in partB.

1H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.69 (s, 1H), 8.57-8.59 (m,1H), 8.38-8.40 (m, 1H), 8.14-8.22 (m, 2H), 7.84-7.86 (m, 1H), 7.66-7.68(m, 1H), 3.99 (s, 2H), 3.56-3.58 (m, 4H), 2.48-2.50 (m, 4H), 2.16 (s,3H). LC-MS: 421.1 [M+1]+, rt=1.242 min

Example 30 (Table 3, Compound 252)

N-(2-cyano-4-(7-fluoro-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide

The title compound was prepared according the procedure for Compound 260(Example 28) starting from reagentN-(2-chloro-4-(7-fluoro-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide by utilizing same procedure in part B. 1HNMR (400 MHz, CDCl₃) δ 8.62 (d, J=8.8 Hz, 1H), 8.50 (s, 1H), 8.37 (d,J=8.9 Hz, 1H), 8.30 (dd, J=9.1, 6.2 Hz, 1H), 7.81 (s, 1H), 7.79-7.71 (m,2H), 7.39-7.31 (m, 1H), 3.96 (s, 2H), 3.75 (d, J=3.8 Hz, 4H), 2.56 (s,4H), 2.32 (s, 3H). LC-MS: 405.2[M+1]⁺, rt=1.116 min

Example 31 (Table 3, Compound 258)

N-(2-cyano-4-(7-methoxy-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide

The title compound was prepared according the procedure for Compound 260(Example 28) starting from reagentN-(2-chloro-4-(7-methoxy-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamideby utilizing same procedure in part B.

1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.68 (s, 1H), 8.56-8.58 (m,1H), 8.383-8.34 (m, 1H), 8.03 (s, 1H), 7.81-7.83 (m, 1H), 7.47-7.48 (m,1H), 7.27-7.29 (m, 1H), 3.95 (s, 5H), 3.56-3.58 (m, 4H), 2.47-2.49 (m,4H), 2.16 (s, 3H). LC-MS: 417.2 [M+1]+, rt=1.110 min

Example 32 (Table 3, Compound 259)

N-(4-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)-2-fluorophenyl)acetamideRAGE-259 (S150097-026)

The title compound was prepared according the procedure for Compound 260(Example 28) starting from reagentN-(4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)-2-fluorophenyl)acetamideby utilizing same procedure in part B.

¹H NMR (400 MHz, DMSO) δ 9.98 (s, 1H), 8.60 (d, 1H), 8.51 (d, 1H), 8.29(s, 1H), 8.21 (dt, 2H), 8.13 (d, 1H), 7.92 (dd, 1H), 4.01 (s, 2H), 3.57(s, 4H), 2.5 (m, 4H), 2.15 (s, 3H). LC-MS: 405.2 [M+1]⁺, rt=1.317 min

Example 33 (Table 3, Compound 237) Part A Synthesis ofN-(4-(4-((butylamino)methyl)quinolin-2-yl)phenyl)acetamide (Compound237)

Step 1: 2-(4-aminophenyl)quinoline-4-carboxylic acid

A solution of 1-(4-aminophenyl)ethan-1-one (27.5 g, 104 mmol) in EtOH(200 mL) was added to a solution of indoline-2,3-dione (20 g, 148 mmol)in 6 M aqueous KOH (200 mL) at 100° C. The reaction was monitored byLC-MS until the starting material was consumed. Then the reactionmixture was concentrated to remove EtOH. The residue was diluted withwater. The pH value of the mixture was acidified to 5 by adding 1Maqueous HCl solution. The precipitate was filtered to give the desiredproduct (28 g, 99%) as red solid.

Step 2: 2-(4-acetamidophenyl)quinoline-4-carboxylic acid

A solution of 2-(4-aminophenyl)quinoline-4-carboxylic acid (10 g, 37.9mmol) in THF was stirred at 0° C. Then DIPEA (7.65 g, 59.3 mmol) wasadded. After that acetyl chloride (3.56 g, 45.6 mmol) was added to thereaction mixture until the starting material was consumed. The reactionmixture was quenched with ice water and extracted with EA, and combinedorganic phase was dried over anhydrous sodium sulfate. The solvent wasconcentrated to give crude title product (yellow solid 7.3 g, 63%).

Step 3: 2-(4-acetamidophenyl)quinoline-4-carboxylic (isobutyl carbonic)anhydride

The mixture of 2-(4-acetamidophenyl)quinoline-4-carboxylic acid (1 g,3.26 mmol), TEA (0.33 g, 3.26 mmol), DMAP (cat 50 mg) and DCM (50 mL)was chilled at 0° C., and then the isobutyl carbonochloridate (0.979 g,7.2 mmol) was added to the reaction mixture. The reaction was monitoredby LC-MS until the starting material was consumed. The reaction mixturewas quenched with ice water and extracted with EA, and combined organicphase was dried over anhydrous sodium sulfate. The solvent wasconcentrated to give crude title product (brown solid 0.72 g, 54%).

Step 4: N-(4-(4-(hydroxymethyl)quinolin-2-yl)phenyl)acetamide

A solution of 2-(4-acetamidophenyl)quinoline-4-carboxylic (isobutylcarbonic) anhydride (200 mg, 0.49 mmol) in THF was stirred at 0° C.NaBH₄ (74.1 mg, 1.95 mmol) was added at 0° C. The reaction was monitoredby LC-MS until the starting material was consumed. The reaction mixturewas quenched with ice water and extracted with EA, and combined organicphase was dried over anhydrous sodium sulfate. The solvent wasconcentrated to give crude title product (yellow solid, 99 mg, 69%).

Step 5: N-(4-(4-formylquinolin-2-yl)phenyl)acetamide

To a solution of N-(4-(4-(hydroxymethyl)quinolin-2-yl)phenyl)acetamide(50 mg, 0.171 mmol) in THF were added Dess-Martin reagent (145 mg, 0.342mmol) and Na₂CO₃ (45.3 mg, 0.427 mmol) at rt. The reaction was monitoredby LC-MS until the starting material was consumed. The reaction mixturewas quenched with ice water and extracted with EA, and combined organicphase was dried over anhydrous sodium sulfate. The solvent wasconcentrated to give crude title product (49 mg, 99%) as a faint yellowsolid.

Step 6: N-(4-(4-((butylamino)methyl)quinolin-2-yl)phenyl)acetamide

A mixture of N-(4-(4-formylquinolin-2-yl)phenyl)acetamide (160 mg, 0.55mmol), 2-methoxyethan-1-amine (40.1 mg, 0.55 mmol), THF (2 drops),acetic acid (2 drops) and DCM (10 mL) was stirred at rt for 1 h. ThenNaBH(OAc)₃ (275 mg, 1.3 mmol) was added and the mixture was stirredovernight. The crude reaction was diluted with DCM, washed withsaturated NaHCO₃ solution and saturated NaCl solution, and then driedover anhydrous sodium sulfate. The organic phase was concentrated andpurified by flash column (SiO₂, Hexane:EA=8:2 to 1:1) to give the titleproduct (157 mg, 82%) as a yellow solid.

Compound 237: N-(4-(4-((butylamino)methyl)quinolin-2-yl)phenyl)acetamide

¹H NMR (400 MHz, MeOD) δ 8.63 (s, 1H), 8.49 (dd, J=21.7, 8.3 Hz, 2H),8.31-8.24 (m, 2H), 8.24-8.19 (m, 1H), 8.05 (ddd, J=8.3, 7.1, 1.0 Hz,1H), 8.03-7.96 (m, 2H), 5.14 (s, 2H), 3.45-3.35 (m, 2H), 2.23 (s, 3H),1.92 (ddd, J=12.9, 10.4, 6.7 Hz, 2H), 1.66-1.49 (m, 2H), 1.07 (t, J=7.4Hz, 3H). MS (ESI, pos. ion) m/z: 348.2 (M+H).

The similar synthetic route was used to the following compounds:

Example 34 (Table 3, Compound 233)

Compound 233:(N-(4-(4-(((2-methoxyethyl)amino)methyl)quinolin-2-yl)phenyl)acetamide)was Prepared from N-(4-(4-formylquinolin-2-yl)phenyl)acetamide and2-methoxyethan-1-amine

¹H NMR (400 MHz, MeOD) δ 8.65 (s, 1H), 8.51 (dd, J=8.3, 4.8 Hz, 2H),8.32-8.25 (m, 2H), 8.25-8.20 (m, 1H), 8.06 (ddd, J=8.3, 7.1, 1.0 Hz,1H), 8.02-7.93 (m, 2H), 5.19 (s, 2H), 3.87 (s, 2H), 3.62 (dd, J=6.4, 3.6Hz, 2H), 3.51 (s, 3H), 2.24 (d, J=12.6 Hz, 3H). MS (ESI, pos. ion) m/z:360.2 (M+H).

Example 35 (Table 3, Compound 239)

Compound 239:(N-(4-(4-(((2-(dimethylamino)ethyl)amino)methyl)quinolin-2-yl)phenyl)acetamide)was Prepared from N-(4-(4-formylquinolin-2-yl)phenyl)acetamide andcorresponding N1,N1-dimethylethane-1,2-diamine

¹H NMR (400 MHz, MeOD) δ 8.76 (s, 1H), 8.56 (d, J=8.2 Hz, 1H), 8.46 (d,J=8.4 Hz, 1H), 8.37-8.29 (m, 2H), 8.28-8.20 (m, 1H), 8.10-8.03 (m, 1H),8.03-7.96 (m, 2H), 5.25 (s, 2H), 3.96 (dd, J=20.2, 14.0 Hz, 2H), 3.80(t, J=6.2 Hz, 2H), 3.16-3.05 (m, 6H), 2.23 (s, 3H). MS (ESI, pos. ion)m/z: 363.3 (M+H).

Example 36 (Table 3, Compound 241)

Compound 241:(N-(4-(4-(((2-(methylamino)ethyl)amino)methyl)quinolin-2-yl)phenyl)acetamide)was Prepared from N-(4-(4-formylquinolin-2-yl)phenyl)acetamide andN1-methylethane-1,2-diamine

¹H NMR (400 MHz, MeOD) δ 8.70 (s, 1H), 8.51 (d, J=8.5 Hz, 1H), 8.42 (d,J=8.4 Hz, 1H), 8.31 (d, J=8.8 Hz, 2H), 8.20 (t, J=7.8 Hz, 1H), 8.06-7.97(m, 3H), 5.17 (s, 2H), 3.77 (t, J=5.7 Hz, 2H), 3.62 (t, J=6.1 Hz, 2H),2.87 (s, 3H), 2.23 (s, 3H). MS (ESI, pos. ion) m/z: 349.2 (M+H).

Example 37 (Table 3, Compound 244)

Compound 244: (tert-butyl4-((2-(4-acetamidophenyl)quinolin-4-yl)methyl)piperazine-1-carboxylate)was Prepared from N-(4-(4-formylquinolin-2-yl)phenyl)acetamide andtert-butyl piperazine-1-carboxylate

¹H NMR (400 MHz, MeOD) δ 10.23 (s, 1H), 8.13-8.59 (m, 5H), 7.68-7.87 (m,4H), 4.93 (s, 2H), 4.04 (br, 2H), 3.25-3.60 (m, 6H), 2.10 (2, 3H), 1.42(s, 9H). MS (ESI, pos. ion) m/z: 461.3 (M+H).

Example 38 (Table 3, Compound 246)

Compound 246:(N-(4-(4-((4-acetylpiperazin-1-yl)methyl)quinolin-2-yl)phenyl)acetamide)was Prepared from N-(4-(4-formylquinolin-2-yl)phenyl)acetamide and1-(piperazin-1-yl)ethan-1-one

¹H NMR (400 MHz, MeOD) δ 9.05 (s, 1H), 5.01-8.50 (m, 8H), 5.25 (s, 2H),3.5-4.01 (m, 8H), 2.23 (s, 3H), 2.18 (s, 3H). MS (ESI, pos. ion) m/z:403.2 (M+H).

Example 39 (Table 3, Compound 235)

Compound 235:(N-(4-(4-((propylamino)methyl)quinolin-2-yl)phenyl)acetamide) wasPrepared from N-(4-(4-formylquinolin-2-yl)phenyl)acetamide andpropan-1-amine

¹H NMR (400 MHz, MeOD) δ 8.62 (s, 1H), 8.52 (d, J=8.4 Hz, 1H), 8.46 (d,J=8.5 Hz, 1H), 8.29-8.25 (m, 2H), 8.23 (t, J=7.8 Hz, 1H), 8.05 (t, J=7.8Hz, 1H), 8.00 (d, J=8.9 Hz, 2H), 5.13 (s, 2H), 3.37 (d, J=7.9 Hz, 2H),2.23 (s, 3H), 1.96 (dq, J=15.1, 7.5 Hz, 2H), 1.14 (t, J=7.4 Hz, 3H). MS(ESI, pos. ion) m/z: 334.2 (M+H).

Example 40 (Table 3, Compound 231)

Compound 231:(N-(4-(4-(((2-hydroxyethyl)amino)methyl)quinolin-2-yl)phenyl)acetamide)was Prepared from N-(4-(4-formylquinolin-2-yl)phenyl)acetamide and2-aminoethan-1-ol

¹H NMR (400 MHz, MeOD) δ 8.65 (s, 1H), 8.53 (d, J=8.3 Hz, 1H), 8.49 (d,J=8.5 Hz, 1H), 8.30-8.22 (m, 3H), 8.09-8.04 (m, 1H), 8.04-7.99 (m, 2H),5.20 (s, 2H), 4.06-4.01 (m, 2H), 3.56-3.50 (m, 2H), 2.23 (s, 3H). MS(ESI, pos. ion) m/z: 336.2 (M+H).

Example 41 (Table 3, Compound 242) Part B: Synthesis ofN-(4-(4-((methyl(2-(methylamino)ethyl)amino)methyl)quinolin-2-yl)phenyl)acetamide

Step 1: N-(4-(4-(chloromethyl)quinolin-2-yl)phenyl)acetamide

The SOCl₂ (17.8 g, 149.6 mmol) was added slowly to the mixtureN-(4-(4-(hydroxymethyl)quinolin-2-yl)phenyl)acetamide (2.5 g, 8.55 mmol,prepared in part A) and DCM (40 mL) at 0° C. for 2.5 h. The reaction wasmonitored by LC-MS until the starting material was consumed. Thesaturated NaHCO₃ solution was added to the reaction mixture at 0° C.until pH value of the solution was 7 and extracted with EA. The combinedorganic phase was dried over anhydrous sodium sulfate. The solvent wasconcentrated to give crude title product (2.32 g, 87%) as a brown solid.

Step 2:N-(4-(4-((methyl(2-(methylamino)ethyl)amino)methyl)quinolin-2-yl)phenyl)-acetamide

A mixture of N-(4-(4-(chloromethyl)quinolin-2-yl)phenyl)acetamide (150mg, 0.48 mmol), N1,N2-dimethylethane-1,2-diamine (42.3 mg, 0.48 mmol)and K₂CO₃ (266.7 mg, 1.93 mmol) in DMF (15 mL) was stirred at rt for 4h. The reaction mixture was quenched with ice water and extracted withEA immediately, and combined organic phase was dried over anhydroussodium sulfate. The organic phase was concentrated and purified by flashcolumn (SiO₂, Hexane:EA=8:2 to 1:1) to give the title product (brownsolid 0.72 g, 73%).

Compound 242:(N-(4-(4-((methyl(2-(methylamino)ethyl)amino)methyl)quinolin-2-yl)phenyl)acetamide)

¹H NMR (400 MHz, MeOD) δ 9.01 (s, 1H), 8.70 (d, J=8.5 Hz, 1H), 8.49 (d,J=8.6 Hz, 1H), 8.34 (t, J=9.4 Hz, 2H), 8.30-8.18 (m, 1H), 8.08 (dd,J=14.0, 6.3 Hz, 1H), 8.00 (d, J=8.9 Hz, 2H), 5.20 (d, J=47.3 Hz, 2H),3.97-3.58 (m, 4H), 3.10-2.90 (m, 3H), 2.86 (d, J=22.0 Hz, 3H), 2.23 (s,3H). MS (ESI, pos. ion) m/z: 363.2 (M+H).

The similar synthetic route was used to the following compounds:

Example 42 (Table 3, Compound 245)

Compound 245:(N-(4-(4-((4-methylpiperazin-1-yl)methyl)quinolin-2-yl)phenyl)acetamide)was Prepared from N-(4-(4-(chloromethyl)quinolin-2-yl)phenyl)acetamideand 1-methylpiperazine

¹H NMR (400 MHz, MeOD) δ 8.29 (d, J=8.3 Hz, 1H), 8.11 (d, J=8.6 Hz, 3H),7.97 (s, 1H), 7.76 (t, J=7.3 Hz, 3H), 7.58 (t, J=7.3 Hz, 1H), 4.10 (s,2H), 3.10 (s, 4H), 2.76 (m, 7H), 2.19 (s, 3H). MS (ESI, pos. ion) m/z:375.2 (M+H).

Part C: Example 43 (Table 3, Compound 234) Synthesis ofN-(4-(4-(((2-methoxyethyl)(methyl)amino)methyl)quinolin-2-yl)phenyl)acetamide

Step 1:2-(4-aminophenyl)-N-(2-methoxyethyl)-N-methylquinoline-4-carboxamide

A mixture of 2-(4-aminophenyl)quinoline-4-carboxylic acid (2 g, 7.6mmol, prepared in part A), 2-methoxy-N-methylethan-1-amine (1.02 g, 11.4mmol), HOBT (2.05 g, 15.2 mmol), EDCI (2.91 g, 15.2 mmol) and DIEA (2.95g, 22.8 mmol) in DCM (30 mL) was stirred at rt for 16 h. Water was addedto the reaction mixture and extracted with EA. The combined organicphase was dried over anhydrous sodium sulfate, and the solvent wasconcentrated to give crude title product (white solid 1.33 g, 52%).

Step 2:4-(4-(((2-methoxyethyl)(methyl)amino)methyl)quinolin-2-yl)aniline

A solution of2-(4-aminophenyl)-N-(2-methoxyethyl)-N-methylquinoline-4-carboxamide(1.1 g, 3.3 mmol) in THF was added to the chilled BH3′THF (1.95 mL, 1.95mmol) at −10° C., and then the mixture was stirred at rt for 2.5 h. Thereaction was monitored by LC-MS until the starting material wasconsumed. The reaction mixture was quenched with ice water and extractedwith EA. The combined organic phase was dried over anhydrous sodiumsulfate and the solvent was concentrated to give crude title product(faint yellow solid, 0.85 g, 81%).

Step 3:N-(4-(4-(((2-methoxyethyl)(methyl)amino)methyl)quinolin-2-yl)phenyl)acetamide

The mixture of4-(4-(((2-methoxyethyl)(methyl)amino)methyl)quinolin-2-yl)aniline (1.1g, 3.4 mmol), TEA (0.33 g, 3.26 mmol) and DCM was stirred at 0° C., andthen the acetyl chloride (0.32 g, 4.1 mmol) was added to the reactionmixture. The reaction was monitored by LC-MS until the starting materialwas consumed (around 2 h). The reaction mixture was quenched with icewater and extracted with EA. The combined organic phase was dried overanhydrous sodium sulfate and the solvent was concentrated to give crude,which was purified by flash column (SiO₂, Hexane:EA=8:2 to 1:1) to givethe title product (yellow solid 1.04 g, 69%).

¹H NMR (400 MHz, MeOD) δ 8.79-8.70 (m, 1H), 8.54 (d, J=8.5 Hz, 1H), 8.47(d, J=8.7 Hz, 1H), 8.32-8.18 (m, 3H), 8.11-7.95 (m, 3H), 5.28 (d, J=69.5Hz, 3H), 3.92 (t, J=4.8 Hz, 2H), 3.68 (s, 2H), 3.52 (s, 3H), 3.09 (d,J=16.1 Hz, 3H), 2.23 (s, 3H). MS (ESI, pos. ion) m/z: 364.2 (M+H).

The similar synthetic route was used to the following compounds:

Follow procedure/ Prepared Step 1 Step 2 Step 3 from Part C, Part C,step 2 (with Part C, step 3 (with materials step 1 BH3) AcCl) Compound2-(4-aminophenyl)quinoline-4- 2-(4-aminophenyl)- 4-(4- 236 carboxylicacid (prepared in part N-methyl-N-((methyl(propyl)amino)methyl)quinolin- A, step 1), and N-methylpropan-propylquinoline-4- 2-yl)aniline 1-amine carboxamide Compound2-(4-aminophenyl)quinoline-4- 2-(4-aminophenyl)- 4-(4- 238 carboxylicacid (prepared in part N-butyl-N- ((butyl(methyl)amino)methyl)quinolin-A, step 1), N-methylbutan-1- methylquinoline-4- 2-yl)aniline aminecarboxamide Compound 2-(4-aminophenyl)quinoline-4- 2-(4-aminophenyl)-2-(((2-(4- 232 carboxylic acid (prepared in part N-(2-hydroxyethyl)-aminophenyl)quinolin-4- A, step 1), 2-(methylamino)ethan-N-methylquinoline-4- yl)methyl)(methyl)amino)ethan- 1-ol carboxamide1-ol Compound 2-(4-aminophenyl)quinoline-4- 2-(4-aminophenyl)-N1-((2-(4- 240 carboxylic acid (prepared in part N-(2-aminophenyl)quinolin- A, step 1), N1,N1,N2- (dimethylamino)ethyl)-4-yl)methyl)- trimethylethane-1,2-diamine N-methylquinoline- N1,N2,N2-4-carboxamide trimethylethane-1,2- diamine Compound2-(4-aminophenyl)quinoline-4- (2-(4- 4-(4-(piperidin-1- 247 carboxylicacid (prepared in part aminophenyl)quinolin- ylmethyl)quinolin-2- A,step 1), piperidine 4-yl)(piperidin-1- yl)aniline yl)methanone CompoundMorpholine, 2-(4-amino-3- (2-(4-amino-3- 2-fluoro-4-(4- 214fluorophenyl)quinoline-4- fluorophenyl)quinolin-4-(morpholinomethyl)quinolin- carboxylic acid (prepared fromyl)(morpholino)methanone 2-yl)aniline indoline-2,3-dione and 1-(4-amino-3-fluorophenyl)ethan-1- one by procedure A, step 1) CompoundMorpholine, 2-(4-amino-3- (2-(4-amino-3- 2-chloro-4-(4- 215chlorophenyl)quinoline-4- chlorophenyl)quinolin-4-(morpholinomethyl)quinolin- carboxylic acid (prepared fromyl)(morpholino)methanone 2-yl)aniline indoline-2,3-dione and 1-(4-amino-3-chlorophenyl)ethan-1- one by procedure A, step 1) Compoundmethoxyphenyl)quinoline-4- 2-(4-amino-3- 2-methoxy-4-(4- 216 carboxylicacid (prepared from methoxyphenyl)quinolin- (morpholinomethyl)quinolin-indoline-2,3-dione and 1-(4- 4-yl)(morpholino)methanone 2-yl)anilineamino-3-methoxyphenyl)ethan-1- one by procedure A, step 1) CompoundMorpholine, 2-(4-amino-3- (2-(4-amino-3- 2-amino-5-(4- 217hydroxyphenyl)quinoline-4- hydroxyphenyl)quinolin-(morpholinomethyl)quinolin- carboxylic acid (prepared from4-yl)(morpholino)methanone 2-yl)phenol indoline-2,3-dione and 1-(4-amino-3-hydroxyphenyl)ethan-1- one by procedure A, step 1) CompoundMorpholine, 2-(4-aminophenyl)- (2-(4-aminophenyl)- 4-(7-fluoro-4- 2257-fluoroquinoline-4-carboxylic 7-fluoroquinolin-4-(morpholinomethyl)quinolin-2- acid (prepared from 6-yl)(morpholino)methanone yl)aniline fluoroindoline-2,3-dione and 1-(4-aminophenyl)ethan-1-one by procedure A, step 1) Compound Morpholine,2-(4-aminophenyl)- (2-(4-aminophenyl)- 4-(7-chloro-4- 2267-chloroquinoline-4-carboxylic 7-chloroquinolin-4-(morpholinomethyl)quinolin- acid (prepared from 6-yl)(morpholino)methanone 2-yl)aniline chloroindoline-2,3-dione and 1-(4-aminophenyl)ethan-1-one by procedure A, step 1) Compound Morpholine,2-(4-aminophenyl)- (2-(4-aminophenyl)- 4-(7-methyl-4- 2277-methylquinoline-4-carboxylic 7-methylquinolin-4-(morpholinomethyl)quinolin- acid (prepared from 6-yl)(morpholino)methanone 2-yl)aniline methylindoline-2,3-dione and 1-(4-aminophenyl)ethan-1-one by procedure A, step 1) Compound Morpholine,2-(4-aminophenyl)- (2-(4-aminophenyl)- 4-(7-methoxy-4- 2287-methoxyquinoline-4-carboxylic 7-methoxyquinolin-4-(morpholinomethyl)quinolin- acid (prepared from 6-yl)(morpholino)methanone 2-yl)aniline methoxyindoline-2,3-dione and 1-(4-aminophenyl)ethan-1-one by procedure A, step 1)

Example 44 (Table 3, Compound 236)

Compound 236:N-(4-(4-((methyl(propyl)amino)methyl)quinolin-2-yl)phenyl)acetamide

¹H NMR (400 MHz, MeOD) δ 8.89 (s, 1H), 8.63 (d, J=8.3 Hz, 1H), 8.49 (d,J=8.1 Hz, 1H), 8.35-8.28 (m, 2H), 8.27-8.20 (m, 1H), 8.07 (ddd, J=8.3,7.1, 1.0 Hz, 1H), 8.03-7.96 (m, 2H), 5.23 (d, J=37.1 Hz, 2H), 3.52-3.36(m, 2H), 3.00 (s, 3H), 2.24 (d, J=10.6 Hz, 3H), 2.08-1.93 (m, 2H), 1.08(t, J=7.4 Hz, 3H). MS (ESI, pos. ion) m/z: 348.2 (M+H).

Example 45 (Table 3, Compound 238)

Compound 238:(N-(4-(4-((butyl(methyl)amino)methyl)quinolin-2-yl)phenyl)acetamide)

¹H NMR (400 MHz, MeOD) δ 8.81 (s, 1H), 8.53 (d, J=8.3 Hz, 1H), 8.40 (d,J=8.2 Hz, 1H), 8.24-8.17 (m, 2H), 8.13 (ddd, J=8.4, 7.1, 1.1 Hz, 1H),7.96 (ddd, J=8.3, 7.1, 1.1 Hz, 1H), 7.90-7.83 (m, 2H), 5.13 (q, J=13.1Hz, 2H), 3.35 (m, 2H), 2.88 (s, 3H), 2.10 (s, 3H), 1.92-1.79 (m, 2H),1.46-1.29 (m, 2H), 0.94 (m, 3H). MS (ESI, pos. ion) m/z: 362.1 (M+H).

Example 46 (Table 3, Compound 232)

Compound 232:(N-(4-(4-(((2-hydroxyethyl)(methyl)amino)methyl)quinolin-2-yl)phenyl)acetamide)

¹H NMR (400 MHz, MeOD) δ 8.78 (s, 1H), 8.60 (d, J=8.3 Hz, 1H), 8.48 (d,J=8.3 Hz, 1H), 8.30-8.26 (m, 2H), 8.25-8.20 (m, 1H), 8.08-8.03 (m, 1H),8.00 (d, J=8.8 Hz, 2H), 5.45 (s, 1H), 5.16 (s, 2H), 4.08 (t, J=5.1 Hz,2H), 3.60 (s, 2H), 3.12 (s, 3H), 2.23 (s, 3H). MS (ESI, pos. ion) m/z:350.2 (M+H).

Example 47 (Table 3, Compound 240)

Compound 240:(N-(4-(4-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)quinolin-2-yl)phenyl)acetamide)

¹H NMR (400 MHz, MeOD) δ 8.96 (s, 1H), 8.67 (d, J=8.5 Hz, 1H), 8.51 (d,J=8.5 Hz, 1H), 8.32 (d, J=8.9 Hz, 2H), 8.25 (t, J=7.8 Hz, 1H), 8.08 (t,J=7.8 Hz, 1H), 7.97 (d, J=8.8 Hz, 2H), 5.35 (s, 2H), 4.02-3.95 (m, 2H),3.49-3.44 (m, 2H), 3.06 (s, 3H), 2.72 (s, 6H), 2.22 (s, 3H). MS (ESI,pos. ion) m/z: 377.2 (M+H).

Example 48 (Table 3, Compound 247)

Compound 247:(N-(4-(4-(piperidin-1-ylmethyl)quinolin-2-yl)phenyl)acetamide)

¹H NMR (400 MHz, MeOD) δ 9.01 (s, 1H), 8.72 (d, J=8.5 Hz, 1H), 8.53 (dd,J=8.5, 3.0 Hz, 1H), 8.33 (d, J=8.8 Hz, 2H), 8.25 (t, J=7.7 Hz, 1H), 8.09(t, J=7.7 Hz, 1H), 7.98 (t, J=8.2 Hz, 2H), 5.19 (s, 2H), 3.65 (d, J=11.7Hz, 2H), 3.38 (d, J=12.1 Hz, 2H), 2.22 (s, 3H), 2.10-1.84 (m, 5H),1.69-1.54 (m, 1H). MS (ESI, pos. ion) m/z: 360.2 (M+H).

Example 49 (Table 3, Compound 214)

Compound 214:(N-(2-fluoro-4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide)

1H NMR (400 MHz, MeOD) δ 8.94 (s, 1H), 8.05-8.69 (m, 7H), 5.30 (s, 2H),4.01 (s, 4H), 3.60 (s, 4H), 2.30 (s, 3H). MS (ESI, pos. ion) m/z: 380.2(M+H).

Example 50 (Table 3, Compound 215)

Compound 215:(N-(2-chloro-4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide)

1H NMR (400 MHz, MeOD) δ 8.82 (s, 1H), 8.05-8.63 (m, 7H), 5.17 (s, 2H),4.01 (s, 4H), 3.56 (s, 4H), 2.30 (s, 3H). MS (ESI, pos. ion) m/z: 396.1(M+H).

Example 51 (Table 3, Compound 216)

Compound 216:(N-(2-methoxy-4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide)

1H NMR (400 MHz, MeOD) δ 7.88-8.98 (m, 8H), 5.17 (s, 2H), 4.17 (s, 3H),4.04 (s, 4H), 3.56 (s, 4H), 2.30 (s, 3H). MS (ESI, pos. ion) m/z: 392.1(M+H).

Example 52 (Table 3, Compound 217)

Compound 217:(N-(2-hydroxy-4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide)

1H NMR (400 MHz, MeOD) δ 8.94 (s, 1H), 7.77-8.36 (m, 8H), 5.22 (s, 2H),4.05 (s, 4H), 3.56 (s, 4H), 2.28 (s, 3H). MS (ESI, pos. ion) m/z: 378.2(M+H).

Example 53 (Table 3, Compound 225)

Compound 225:(N-(4-(7-fluoro-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide)

1H NMR (400 MHz, MeOD) δ 8.93 (s, 1H), 7.86-8.78 (m, 7H), 5.20 (s, 2H),4.01 (s, 4H), 3.56 (s, 4H), 2.30 (s, 3H). MS (ESI, pos. ion) m/z: 380.2(M+H).

Example 54 (Table 3, Compound 226)

Compound 226:(N-(4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide)

1H NMR (400 MHz, MeOD) δ 8.52 (s, 1H), 7.76-8.51 (m, 7H), 4.95 (s, 2H),3.87 (s, 4H), 3.39 (s, 4H), 2.10 (s, 3H). MS (ESI, pos. ion) m/z: 396.1(M+H).

Example 55 (Table 3, Compound 227)

Compound 227:(N-(4-(7-methyl-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide)

1H NMR (400 MHz, MeOD) δ 8.72 (s, 1H), 7.79-8.43 (m, 7H), 5.04 (s, 2H),3.91 (s, 4H), 3.41 (s, 4H), 2.63 (s, 3H), 2.11 (s, 3H). MS (ESI, pos.ion) m/z: 376.2 (M+H).

Example 56 (Table 3, Compound 228)

Compound 228:(N-(4-(7-methoxy-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide)

1H NMR (400 MHz, MeOD) δ 8.61 (s, 1H), 7.64-8.56 (m, 7H), 5.06 (s, 2H),4.01 (s, 4H), 4.00 (s, 3H), 3.47 (s, 4H), 2.23 (s, 3H). MS (ESI, pos.ion) m/z: 392.2 (M+H).

Example 57 (Table 3, Compound 219) Part D: Synthesis of2-hydroxy-N-(4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide

A solution of 4-(4-(morpholinomethyl)quinolin-2-yl)aniline (170 mg, 0.53mmol) (which was synthesized by similar procedure in Part A fromindoline-2,3-dione and 1-(4-aminophenyl)ethan-1-one), 2-hydroxyaceticacid (162 mg, 2.13 mmol), EDCI (510 mg, 2.66 mmol), HOBt (359 mg 2.66mmol) in THF (25 mL) was stirred at r.t. overnight. The solution wasconcentrated to remove THF and diluted with EA (100 mL), and thenorganic layer was washed with NaHCO₃ aq. (100 mL×2), brine (100 mL×1).The organic layer was concentrated and purified by prep-HPLC (50 mg,25%).

Compound 219(2-hydroxy-N-(4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide)

¹H NMR (400 MHz, MeOD) δ 8.96 (s, 1H), 8.68 (d, J=8.4 Hz, 1H), 8.48 (d,J=8.3 Hz, 1H), 8.35 (d, J=8.9 Hz, 2H), 8.23 (t, J=7.4 Hz, 1H), 8.12-8.04(m, 3H), 5.21 (s, 2H), 4.22 (s, 2H), 4.04 (s, 4H), 3.56 (s, 4H). MS(ESI, pos. ion) m/z: 378.2 (M+H).

The similar synthetic route was used to the following compounds:

Example 58 (Table 3, Compound 220)

Compound 220:(2-methoxy-N-(4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide) wasPrepared from 4-(4-(morpholinomethyl)quinolin-2-yl)aniline and2-methoxyacetic acid

¹H NMR (400 MHz, MeOD) δ 8.93 (s, 1H), 8.67 (d, J=8.3 Hz, 1H), 8.47 (d,J=8.2 Hz, 1H), 8.38-8.30 (m, 2H), 8.22 (dt, J=19.0, 5.8 Hz, 1H),8.11-8.02 (m, 3H), 5.20 (s, 2H), 4.14 (s, 2H), 4.04 (s, 4H), 3.58-3.54(m, 4H), 3.54 (s, 3H). MS (ESI, pos. ion) m/z: 392.2 (M+H).

Example 59 (Table 3, Compound 223)

Compound 223:(N-(4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)propionamide) wasPrepared from 4-(4-(morpholinomethyl)quinolin-2-yl)aniline and propionicacid

¹H NMR (400 MHz, MeOD) δ 8.60 (s, 1H), 8.53 (d, J=8.2 Hz, 1H), 8.36 (d,J=8.5 Hz, 1H), 8.27 (d, J=8.8 Hz, 2H), 8.13-8.07 (m, 1H), 7.95 (d, J=8.7Hz, 3H), 5.03 (s, 2H), 3.96 (s, 4H), 3.45 (s, 4H), 2.51 (q, J=7.7 Hz,2H), 1.26 (t, J=7.6 Hz, 3H). MS (ESI, pos. ion) m/z: 376.2 (M+H).

Example 60 (Table 3, Compound 224)

Compound 224:(N-(4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)isobutyramide) wasPrepared from 4-(4-(morpholinomethyl)quinolin-2-yl)aniline andisobutyric acid

¹H NMR (400 MHz, MeOD) δ 8.90 (s, 1H), 8.66 (d, J=8.5 Hz, 1H), 8.45 (d,J=8.6 Hz, 1H), 8.33 (d, J=8.8 Hz, 2H), 8.21 (t, J=7.8 Hz, 1H), 8.08-7.99(m, 3H), 5.18 (s, 2H), 4.03 (s, 4H), 3.54 (s, 4H), 2.74 (m, 2.78-2.70,1H), 1.27 (s, 3H), 1.25 (s, 3H). MS (ESI, pos. ion) m/z: 390.2 (M+H).

Example 61 (Table 3, Compound 221)

Compound 221:(2-amino-N-(4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide) StepA: tert-butyl(2-((4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)amino)-2-oxoethyl)carbamatewas Prepared from 4-(4-(morpholinomethyl)quinolin-2-yl)aniline and(tert-butoxycarbonyl)glycine by Similar Procedure in Part D Step B:(2-amino-N-(4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide) wasprepared from tert-butyl(2-((4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)amino)-2-oxoethyl)carbamateby similar procedure in part G, step 4. (Remove Boc Group)

¹H NMR (400 MHz, MeOD) δ 9.01 (s, 1H), 8.69 (d, J=8.5 Hz, 1H), 8.49 (d,J=8.5 Hz, 1H), 8.40 (d, J=8.8 Hz, 2H), 8.22 (t, J=7.8 Hz, 1H), 8.11-8.00(m, 3H), 5.22 (s, 2H), 4.08-4.02 (m, 4H), 3.99 (s, 2H), 3.59-3.53 (m,4H). MS (ESI, pos. ion) m/z: 377.2 (M+H).

Example 62 (Table 3, Compound 222)

Compound 222:(2-acetamido-N-(4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide)was Prepared from 4-(4-(morpholinomethyl)quinolin-2-yl)aniline andacetylglycine

¹H NMR (400 MHz, MeOD) δ 8.96 (s, 1H), 8.69 (d, J=8.5 Hz, 1H), 8.49 (d,J=8.5 Hz, 1H), 8.33 (d, J=8.8 Hz, 2H), 8.22 (t, J=7.8 Hz, 1H), 8.07 (t,J=7.7 Hz, 1H), 7.96 (d, J=8.5 Hz, 2H), 5.22 (s, 2H), 4.09 (s, 2H), 4.05(s, 4H), 3.57 (s, 4H), 2.09 (s, 3H). MS (ESI, pos. ion) m/z: 419.2(M+H).

Part E: Example 63 (Table 3, Compound 218) Synthesis ofN-(2-cyano-4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide

To a mixture ofN-(2-chloro-4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide(Example 50) (NYU215, 600 mg, 1.51 mmol) in DMAC (10 mL), were addedZn(CN)₂ (159 mg, 1.36 mmol), Xphos (322 mg, 0.678 mmol), [(ally)PdCl]₂(123 mg, 0.339 mmol). The reaction was heated at 120° C. for 16 h. Thereaction mixture was quenched with ice water and extracted with EA. Thecombined organic phase was dried over anhydrous sodium sulfate. Thecrude was purified by flash column (SiO₂, Hexane:EA=8:2 to 1:1) to givethe title product (58 mg, 10%).

¹H NMR (400 MHz, MeOD) δ 8.58 (s, 1H), 7.62-8.50 (m, 7H), 4.08 (s, 2H),3.73 (br, 4H), 2.61 (br, 4H), 2.27 (s, 3H). MS (ESI, pos. ion) m/z:387.2 (M+H).

Example 64 (Table 3, Compound 229) Synthesis ofN-(4-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide

Step 1: 2-(4-aminophenyl)-4-(morpholinomethyl)quinoline-7-carbonitrilewas synthesized from4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)aniline (prepared in thesynthesis of Compound 226, Step 2 in the combined table) by utilizingsimilar procedure in NYU 218. The title target was purified by flashcolumn (SiO₂, Hexane:EA=8:2 to 1:1).

Step 2: N-(4-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide(Compound 229) was synthesized from2-(4-aminophenyl)-4-(morpholinomethyl)quinoline-7-carbonitrile and AcCl(by utilizing procedure in Part C, 3^(rd) step)

¹H NMR (400 MHz, MeOD) δ 8.77 (s, 1H), 7.85-8.68 (m, 7H), 5.08 (s, 2H),3.95-4.04 (br, 4H), 3.52 (br, 4H), 2.21 (s, 3H). MS (ESI, pos. ion) m/z:387.2 (M+H).

Example 65 (Table 3, Compound 230) Synthesis of2-(4-acetamidophenyl)-4-(morpholinomethyl)quinoline-7-carboxamide

Step 1: 2-(4-aminophenyl)-4-(morpholinomethyl)quinoline-7-carboxamide

The solution of2-(4-aminophenyl)-4-(morpholinomethyl)quinoline-7-carbonitrile (300 mg,0.872 mmol) (which was prepared in Compound 229, 1^(st) step) in 85%H₂SO₄ was heated at 80° C. for 2 h. The reaction mixture was quenchedwith ice water and the pH value of the mixture was justified to 5 byadding sat. NaHCO₃ (aq). The precipitate was filtered to give theproduct 2-(4-aminophenyl)-4-(morpholinomethyl)quinoline-7-carboxamide(290 mg).

Step 2:2-(4-acetamidophenyl)-4-(morpholinomethyl)quinoline-7-carboxamide

2-(4-acetamidophenyl)-4-(morpholinomethyl)quinoline-7-carboxamide wasprepared from2-(4-aminophenyl)-4-(morpholinomethyl)quinoline-7-carboxamide and AcC1by similar procedure in part C (last step).

¹H NMR (400 MHz, MeOD) δ 8.79 (s, 1H), 7.89-8.79 (m, 7H), 5.08 (s, 2H),3.99 (br, 4H), 3.52 (br, 4H), 2.21 (s, 3H). MS (ESI, pos. ion) m/z:405.2 (M+H).

Example 66 (Table 3, Compound 243) Part F: Synthesis ofN-(4-(4-(3-morpholinopropyl)quinolin-2-yl)phenyl)acetamide

Step 1: methyl (E)-3-(2-(4-acetamidophenyl)quinolin-4-yl)acrylate

The mixture of N-(4-(4-formylquinolin-2-yl)phenyl)acetamide (2 g, 6.9mmol, prepared in part A, step 1-5), methyl(triphenylphosphoranylidene)acetate (2.42 g, 7.24 mmol), DCM (80 mL) wasstirred at r.t. for about 2 h. After reaction, the mixture wasconcentrated to remove DCM, and the residue was diluted with EA (400mL). The organic phase was washed with NaHCO₃ aq. (200 mL), brine (200mL). The organic layer was concentrated and purified by columnchromatography to get crude product (2.2 g, 92%).

Step 2: methyl 3-(2-(4-acetamidophenyl)quinolin-4-yl)propanoate

The mixture of methyl (E)-3-(2-(4-acetamidophenyl)quinolin-4-yl)acrylate(2 g, 5.78 mmol), Pd/C (0.2 g), MeOH (30 mL) was stirred under H₂atmosphere at r.t. overnight. After reaction, the mixture was filteredand washed with MeOH. The solution was concentrated to remove MeOH. Theresidue was diluted with EA (200 mL), and washed with NaHCO₃ aq. (100mL×1), brine (100 mL×2). Organic phase was concentrated and purified bycolumn chromatography to get product (1.91 g, 95%).

Step 3: N-(4-(4-(3-hydroxypropyl)quinolin-2-yl)phenyl)acetamide

N-(4-(4-(3-hydroxypropyl)quinolin-2-yl)phenyl)acetamide was preparedfrom methyl 3-(2-(4-acetamidophenyl)quinolin-4-yl)propanoate by similarprocedure in part a, step 4.

Step 4: N-(4-(4-(3-chloropropyl)quinolin-2-yl)phenyl)acetamide

N-(4-(4-(3-chloropropyl)quinolin-2-yl)phenyl)acetamide was prepared fromN-(4-(4-(3-hydroxypropyl)quinolin-2-yl)phenyl)acetamide by similarprocedure in Part B, step 1.

Step 5: N-(4-(4-(3-morpholinopropyl)quinolin-2-yl)phenyl)acetamide

N-(4-(4-(3-morpholinopropyl)quinolin-2-yl)phenyl)acetamide was preparedfrom N-(4-(4-(3-chloropropyl)quinolin-2-yl)phenyl)acetamide andmorpholine by similar procedure in part b, step 2.

¹H NMR (400 MHz, MeOD) δ 8.58 (d, J=8.2 Hz, 1H), 8.41 (d, J=8.4 Hz, 1H),8.39 (s, 1H), 8.23-8.16 (m, 3H), 8.04-7.97 (m, 3H), 4.08 (dd, J=13.1,3.5 Hz, 2H), 3.93-3.83 (m, 2H), 3.63-3.54 (m, 4H), 3.49-3.40 (m, 2H),3.22 (td, J=12.2, 3.5 Hz, 2H), 2.49-2.37 (m, 2H), 2.23 (s, 3H). MS (ESI,pos. ion) m/z: 390.2 (M+H).

Part G: Example 67 (Table 3, Compound 248) Synthesis of4-((2-(2-methyl-1H-benzo[d]imidazol-6-yl)quinolin-4-yl)methyl)morpholine

Step 1-2: 4-((2-chloroquinolin-4-yl)methyl)morpholine was Prepared from2-chloroquinoline-4-carboxylic acid by Similar Procedure as Described inPart C (the 1^(st) and 2^(nd) Steps) Step 3: tert-butyl2-methyl-6-(4-(morpholinomethyl)quinolin-2-yl)-1H-benzo[d]imidazole-1-carboxylate

A mixture of the compound 4-((2-chloroquinolin-4-yl)methyl)morpholine(1.0 g, 3.82 mmol), tert-butyl2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-1-carboxylate(1.37 g, 3.82 mmol, cas: 1300582-55-1), NaHCO₃ (0.97 g, 11.5 mmol) andPd(PPh₃)₄ (439 mg, 0.38 mmol) in DME (45 mL) and H₂O (15 mL) wasdegassed and then heated at 98° C. under N₂ for 3 hours before beingcooled down. The volatiles were evaporated. The residue was taken up indichloromethane and filtered. The filtrate was directly purified bychromatography (silica, hexanes-ethyl acetate) to give the desiredcompound. Yellow solid (300 mg).

Step 4:4-((2-(2-methyl-1H-benzo[d]imidazol-6-yl)quinolin-4-yl)methyl)morpholine

The solution of tert-butyl2-methyl-6-(4-(morpholinomethyl)quinolin-2-yl)-1H-benzo[d]imidazole-1-carboxylate(300 mg, 0.65 mmol) in HCl/Dixoane (5 mL) was stirred under N₂atmosphere at rt. The volatiles were evaporated. The residue wasdirectly purified by Prep-HPLC to give the desired compound. Yellowsolid (30 mg).

¹H NMR (400 MHz, MeOD) δ 8.94 (s, 1H), 8.83 (s, 1H), 7.95-8.41 (m, 6H),5.17 (s, 2H), 4.04 (br, 4H), 3.54-3.56 (m, 4H), 2.96 (s, 3H). MS (ESI,pos. ion) m/z: 359.2 (M+H).

Example 68 (Table 3, Compound 249) Compound 249:(2-methyl-6-(4-(morpholinomethyl)quinolin-2-yl)benzo[d]oxazole)

Compound 249(2-methyl-6-(4-(morpholinomethyl)quinolin-2-yl)benzo[d]oxazole) wasPrepared from 2-chloroquinoline-4-carboxylic acid and2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole(cas: 1408089-23-5) by similar procedure for Compound 248 (Example 67)(3rd step: coupling reaction, 1^(st) and 2^(nd) step reaction:condensation and reduction).

¹H NMR (400 MHz, MeOD) δ 8.41 (s, 1H), 7.62-8.40 (m, 7H), 4.31 (s, 2H),3.74-3.76 (m, 4H), 2.72 (s, 3H), 2.67 (br, 4H), 2.96. MS (ESI, pos. ion)m/z: 360.2 (M+H).

Assay Methods Primary Screen (High-Throughput Screening Assay)

Primary screening was a two-step process in which compounds were firsttested in a high throughput assay at one concentration (10 uM).Compounds that reduced binding of RAGE tail (ctRAGE) by at least 50%were then selected and subjected to 4-point dose response (10 uM, 1 uM,0.1 uM and 0.01 uM). Compounds that demonstrated a clear dose dependencewere then selected for secondary screening.

Secondary Screen

The goal of the secondary screening was to observe direct binding ofcompounds to ctRAGE. To form a compound-RAGE tail complex, the inventorsadded 5 uM of each compound dissolved in DMSO to 500 uL of 5 uMuniformly ¹⁵N-labeled RAGE tail in 10 mM potassium phosphate buffer, pH6.5. The changes caused by compound binding to RAGE tail were monitoredby using heteronuclear NMR experiment, ¹⁵N-HSQC. This experimentfacilitates monitoring chemical changes of backbone amide protons andnitrogens of RAGE tail due to compound binding (See below) [11].

The method used herein has been described by Rai et al. (J Biol Chem287, 5133-5144), the entire content of which is incorporated herein inits entirety.

High resolution NMR spectroscopy is widely used to screen small moleculelibraries. By using a technique called chemical shift perturbation, NMRspectroscopy provides a relatively fast and direct way toobserve/identify the binding epitopes of a protein for a small molecule.Each NMR active nucleus, ¹H, ¹³C and ¹⁵N, in a ¹³C and/or ¹⁵N-labeledprotein, exhibits a unique chemical shift that reflects its chemicalenvironment in the molecular structure, and is exquisitely sensitive tochanges in that environment caused by small molecule binding to theprotein. Standard NMR assignment procedures the inventors to determinethe chemical shifts for all NMR active nuclei in the protein ofinterest. Since changes in these chemical shifts reflect structuralchanges in the immediate vicinity of the small molecule binding site onthe protein, quantifying the changes and mapping affected amino acids onthe 3D protein structure unambiguously confirm the binding event andalso define the small molecule-protein interaction surface at atomicresolution.

NMR spectroscopy allows the inventors to estimate binding affinitiesdepending on the magnitude of the chemical shift change AQ and the rateconstant, k_(off), between bound and free states. Chemical exchange canresult in gradual changes of chemical shifts when ΔΩ<<k_(off) (fastexchange), line broadening when ΔΩ≤k_(off) (intermediate exchange) orthe appearance of new peaks when ΔΩ>>k_(off) (slow exchange). Assumingthat the binding reaction is diffusion limited and the average change ofthe ¹H chemical shift is ˜0.1 ppm, the fast exchange regime will occurwhen the dissociation constant, K_(d), is larger than 100 uM andintermediate or slow exchange will occur when the dissociation constantis less than or equal to 10 uM. Binding stoichiometry can be establishedwhen no further changes in the chemical shifts or differentialbroadening of specific peaks in the NMR spectra occur as the molar ratioof small molecule to protein increases. The binding affinities can beestimated by using the complementary method of surface plasmon resonance(SPR) and/or fluorescence titration.

To distinguish ¹⁵N- and/or ¹³C-labeled protein NMR signals from thoseoriginating from a small molecule, the chemical shift perturbationtechnique employs a ¹⁵N and/or ¹³C edited experiment known asheteronuclear single quantum coherence (HSQC). Each peak in the HSQCspectrum corresponds to a ¹H-¹⁵N and/or ¹H-¹³C bond in the protein. A700 MHz NMR spectrometer equipped with an ultrasensitive cryoprobe isused to conduct the assays; the combination of high magnetic field and acryoprobe significantly improves the sensitivity of NMR experiments.

Procedure

There are two possible modes of blocking complex formation between RAGEtail and the FH1 domain of Dia-1: A small molecule binds either to RAGEtail or the FH1 domain and obstructs the RAGE tail—FH1 interactionsurface. RAGE tail is a small, 43 amino acid peptide. It is onlypartially folded. A solution structure of a N-terminal fragment of RAGEtail is determined by the inventors. The FH1 domain is a 260 amino acidfragment of Dia-1 containing multiple polyproline stretches. Accordingto the preliminary results, FH1 does not have a well-defined tertiarystructure. Based on our preliminary results, the ¹⁵N-HSQC spectra ofboth free ¹⁵N-CT-RAGE and the ¹⁵N-CT-RAGE-FH1 complex contain wellresolved peaks that have been assigned to facilitate chemical shiftperturbation screening. Thus, for the first round of the screen (FIG.1), the ¹⁵N-HSQC spectral changes of either free ¹⁵N-CT-RAGE or a¹⁵N-CT-RAGE-FH1 complex induced by small molecule binding are observed.The screenings are conducted by titrating up to 10 μM of a smallmolecule to 10 μM of the protein sample; small molecules that bind toCT-RAGE or FH1 with affinities weaker than 10 μM are unlikely be ofinterest for biological studies and are not pursued.

In general, if a small molecule binds to CT-RAGE then correspondingchanges in the ¹⁵N-HSQC spectrum of free ¹⁵N-CT-RAGE will be observed.

If a small molecule binds to the FH1 domain then no changes will beobserved in the ¹⁵N-HSQC spectrum of free ¹⁵N-CT-RAGE. However, specificchanges in the ¹⁵N-HSQC spectrum of ¹⁵N-CT-RAGE-FH1 will be observed.

At the titration endpoint, the ¹⁵N-HSQC spectrum of ¹⁵N-CT-RAGE-FH1 willbe similar to the spectrum of free ¹⁵N-CT-RAGE.

Binding affinities of small molecules for either CT-RAGE or FH1 aredetermined by performing fluorescence titrations to generate bindingisotherms and standard SPR experiments.

FIG. 2 shows that compounds of the RAGE inhibitors inhibit RAGEligand-stimulated inflammatory gene expression in primary murine aorticendothelial cells.

FIG. 3 shows that compounds of the RAGE inhibitors inhibit RAGEligand-stimulated inflammatory gene expression in human THP1macrophage-like cells.

FIG. 4 shows that compounds of the RAGE inhibitors inhibit RAGEligand-stimulated migration of aortic smooth muscle cells (SMCs).

Results presented in the FIGS. 2-4 reveal that in the threeabove-indicated cell types, which are perturbed by RAGE ligands indiseases associated with RAGE ligand accumulation, inhibition ofRAGE-DIAPH1 interaction using the small molecules discovered andreported herein blocks the adverse effects of RAGE ligands on cellularperturbation in these vascular and immune cells. These data providesignificant evidence of the ability of the compounds to suppressvascular and inflammatory cell perturbation that is characteristic ofthe chronic diseases in which RAGE ligands accumulate.

EXAMPLES

As detailed above, in order to identify small molecules to antagonizeRAGE activity, the present inventors developed primary screening assay.

From screening a chemical compounds library consisting of 59,000compounds, a number of compounds were identified as small moleculeinhibitors for the RAGE activity.

Example B1 Representative Method and Protocol for Primary Screening Day1

-   -   Step 1. Add 50 μl anti-DIAPH1 (1:160 dilution in 0.1M NaHCO₃ pH        9.6)/well. Incubate overnight at 4° C.

Day 2

-   -   Step 2. Use the plate washer to aspirate anti-DIAPH11 and wash        plates 4× with PBS 100 μl per well per wash.    -   Step 3. Add 180 μl 3% BSA in 1×PBS. Incubate for 1.5 hrs at room        temperature Step 4. Use the plate washer to aspirate the        blocking solution and wash 5× with PBS 300 μl per well.    -   Step 5. Add 50 μl of DIAPH1 containing lysate (85 μg) and        incubate at RT for 3 hours.    -   Step 6. Aspirate the lysate and wash the plate 5×(100 μl) on the        plate washer.    -   Step 7. Add 25 μl PBS to the wells.    -   Step 8. Add 0.5 μL compound per well.    -   Step 9. Add 24.5 μL GFP RAGE tail (125 nM) into each well for 2        hrs at room temperature.    -   Step 10. Aspirate and wash 5× with PBS (100 μL) on the plate        washer.    -   Step 11. Add 100 μl PBS in each well.    -   Step 12. Detection: Read on fluorescence plate reader excitation        435 nm and 485 nm emission

Compounds that blocked the binding of RAGE tail to DIAPH1 by 50% or morewere subjected to 4 point dose response: 10 μM, 1 μM, 0.1 μM and 0.01μM.

Compounds that showed dose dependence were then subjected to secondaryscreen:

K_(d) Determinations

A number of representative quinoline compounds of this invention are orcan be tested for their inhibitory activity. The quinoline compounds ofthe invention along with their available K_(d) values and/or %inhibition values, as determined using conventional methods to thoseskilled in the art, are listed below in Table 1.

TABLE 1 Exemplary Quinoline Compounds and % Inhibition Values Compd MW %Inhibition Kd # Structure (Calcd) @ 10 μM μM  1

293.33 51 ND  2

277.33 27 ND  3

361.45 36 ND  4

376.46 45 56 +/− 5   5

375.43 34 41 +/− 7   6

363.42 17 99 +/− 12  7

359.43 29 77 +/− 10  8

264.29 64 ND  9

306.32 25 ND 10

277.33 28 ND 11

276.34 34 ND

TABLE 2 Additional Exemplary Quinoline Compounds and % Inhibition ValuesCompd MW % Inhibition Kd # Structure (Calcd) @ 12.5 μM μM 101

409.88 27 43 +/− 10 102

410.86 37 29 +/− 12 103

410.86 38 18 +/− 6  104

409.88 37 60 +/− 20 105

410.86 32 45 +/− 12 106

410.86 35 34 +/− 12 107

347.42 31 44 +/− 15 108

361.45 44 11 +/− 5  109

362.44 20 1.9 +/− 0.5 110

395.89 20 ND 111

396.88 18 ND 112

375.47 27 ND 113

375.47 ND ND

TABLE 3 Further Additional Exemplary Quinoline Compounds Com- poundExample # # Name 214 Example(N-(2-fluoro-4-(4-(morpholinomethyl)quinolin-2- 49 yl)phenyl)acetamide)215 Example (N-(2-chloro-4-(4-(morpholinomethyl)quinolin-2- 50yl)phenyl)acetamide) 216 Example(N-(2-methoxy-4-(4-(morpholinomethyl)quinolin-2- 51 yl)phenyl)acetamide)217 Example (N-(2-hydroxy-4-(4-(morpholinomethyl)quinolin-2- 52yl)phenyl)acetamide) 218 ExampleN-(2-cyano-4-(4-(morpholinomethyl)quinolin-2- 63 yl)phenyl)acetamide 219Example (2-hydroxy-N-(4-(4-(morpholinomethyl)quinolin-2- 57yl)phenyl)acetamide) 220 Example(2-methoxy-N-(4-(4-(morpholinomethyl)quinolin-2- 58 yl)phenyl)acetamide)221 Example (2-amino-N-(4-(4-(morpholinomethyl)quinolin-2- 61yl)phenyl)acetamide) 222 Example(2-acetamido-N-(4-(4-(morpholinomethyl)quinolin-2- 62yl)phenyl)acetamide) 223 Example (N-(4-(4-(morpholinomethyl)quinolin-2-59 yl)phenyl)propionamide) 224 Example(N-(4-(4-(morpholinomethyl)quinolin-2- 60 yl)phenyl)isobutyramide) 225Example (N-(4-(7-fluoro-4-(morpholinomethyl)quinolin-2- 53yl)phenyl)acetamide) 226 Example(N-(4-(7-chloro-4-(morpholinomethyl)quinolin-2- 54 yl)phenyl)acetamide)227 Example (N-(4-(7-methyl-4-(morpholinomethyl)quinolin-2- 55yl)phenyl)acetamide) 228 Example(N-(4-(7-methoxy-4-(morpholinomethyl)quinolin-2- 56 yl)phenyl)acetamide)229 Example N-(4-(7-cyano-4-(morpholinomethyl)quinolin-2- 64yl)phenyl)acetamide 230 Example 2-(4-acetamidophenyl)-4- 65(morpholinomethyl)quinoline-7- carboxamide 231 Example(N-(4-(4-(((2-hydroxyethyl)amino)methyl)quinolin-2- 40yl)phenyl)acetamide) 232 Example (N-(4-(4-(((2- 46hydroxyethyl)(methyl)amino)methyl)quinolin-2- yl)phenyl)acetamide) 233Example N-(4-(4-(((2-methoxyethyl)amino)methyl)quinolin-2- 34yl)phenyl)acetamide) 234 Example (N-(4-(4-(((2- 43methoxyethyl)(methyl)amino)methyl)quinolin-2- yl)phenyl)acetamide 235Example (N-(4-(4-((propylamino)methyl)quinolin-2- 39yl)phenyl)acetamide) 236 ExampleN-(4-(4-((methyl(propyl)amino)methyl)quinolin-2- 44 yl)phenyl)acetamide237 Example N-(4-(4-((butylamino)methyl)quinolin-2- 33yl)phenyl)acetamide 238 Example(N-(4-(4-((butyl(methyl)amino)methyl)quinolin-2- 45 yl)phenyl)acetamide)239 Example (N-(4-(4-(((2- 35(dimethylamino)ethyl)amino)methyl)quinolin-2- yl)phenyl)acetamide) 240Example (N-(4-(4-(((2- 47(dimethylamino)ethyl)(methyl)amino)methyl)quinolin-2-yl)phenyl)acetamide) 241 Example (N-(4-(4-(((2- 36(methylamino)ethyl)amino)methyl)quinolin- 2-yl)phenyl)acetamide) 242Example (N-(4-(4-((methyl(2- 41(methylamino)ethyl)amino)methyl)quinolin-2- yl)phenyl)acetamide) 243Example N-(4-(4-(3-morpholinopropyl)quinolin-2- 66 yl)phenyl)acetamide244 Example (tert-butyl 4-((2-(4-acetamidophenyl)quinolin-4- 37yl)methyl)piperazine-1-carboxylate) 245 Example(N-(4-(4-((4-methylpiperazin-1-yl)methyl)quinolin-2- 42yl)phenyl)acetamide) 246 Example(N-(4-(4-((4-acetylpiperazin-1-yl)methyl)quinolin-2- 38yl)phenyl)acetamide) 247 Example(N-(4-(4-(piperidin-1-ylmethyl)quinolin-2- 48 yl)phenyl)acetamide) 248Example 4-42-(2-methyl-1H-benzo[d]imidazol-6- 67yl)quinolin-4-yl)methyl)morpholine 249 Example(2-methyl-6-(4-(morpholinomethyl)quinolin-2- 68 yl)benzo[d]oxazole) 250Example N-(2-fluoro-4-(7-fluoro-4- 22 (morpholinomethyl)quinolin-2-yl)phenyl)acetamide 251 Example N-(2-chloro-4-(7-fluoro-4- 23(morpholinomethyl)quinolin-2- yl)phenyl)acetamide 252 ExampleN-(2-cyano-4-(7-fluoro-4- 30 (morpholinomethyl)quinolin-2-yl)phenyl)acetamide 253 ExampleN-(4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)-2- 24fluorophenyl)acetamide 254 Example N-(2-chloro-4-(7-chloro-4- 21(morpholinomethyl)quinolin-2- yl)phenyl)acetamide 255 ExampleN-(4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)-2- 29cyanophenyl)acetamide 256 Example N-(2-fluoro-4-(7-methoxy-4- 25(morpholinomethyl)quinolin- 2-yl)phenyl)acetamide 257 ExampleN-(2-chloro-4-(7-methoxy-4- 26 (morpholinomethyl)quinolin-2-yl)phenyl)acetamide 258 Example N-(2-cyano-4-(7-methoxy-4- 31(morpholinomethyl)quinolin- 2-yl)phenyl)acetamide 259 ExampleN-(4-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)-2- 32fluorophenyl)acetamide 260 Example N-(2-chloro-4-(7-cyano-4- 28a(morpholinomethyl) quinolin-2- yl)phenyl)acetamide 261 ExampleN-(2-cyano-4-(7-cyano-4- 28b (morpholinomethyl)quinolin-2-yl)phenyl)acetamide 262 ExampleN-(4-(7-ethoxy-4-(morpholinomethyl)quinolin-2- 27yl)-2-fluorophenyl)acetamide

Example B2 Representative In Vitro Assays Methods and Materials

The effects of compounds described herein on murine smooth muscle cellmigration can be determined using the following system. Primary murineaortic smooth muscles retrieved from wild type C57BL/6 mice are grown to90% confluency in medium containing 10% fetal bovine serum. Cells areserum starved for 16 hrs during which time fetal bovine serum isreplaced with 0.1% bovine serum albumin. Following this period of serumstarvation, cells are pre-treated for 1.5 hours with a compound asdescribed herein at a concentration of 1 μM. At the end of that time,compounds are removed and cell monolayers are vertically scratched witha pipet tip to create a “wound” and then RAGE ligand carboxy methyllysine human serum albumin (CML AGE), 100 μg/ml, is added for 7 hrs.Photographs of the monolayer can be taken at time 0 (time of scratch/CMLAGE) and at 7 hrs. The ingrowth of the cells is then noted and % areaingrowth calculated comparing ingrowth at baseline to that at 7 hrs.Experients are typically performed in triplicate experiments.

Fluorescence Binding Assay

Native tryptophan fluorescence experiments were conducted using a HoribaJobin Yvon Fluorolog spectrofluorometer. 1 mM of compound was dissolvedin 10 mM phosphate buffer [pH 7.0] and 50% DMSO. ctRAGE was bacteriallyexpressed and purified as described¹. 10 nM ctRAGE solution wasindividually titrated from 0.1 nM-100 μM with the compounds in 100 μL of10 mM phosphate buffer [pH 7.0] and 5% DMSO. The excitation and emissionwavelengths were 280 nm and 352 nm, respectively. Dissociationconstants, K_(d), were estimated from the changes in peak fluorescenceintensities as a function of the free compound concentration by usingPrism 5 software (GraphPad). Data were fit to the equation,(F−F₀)/F_(max)=[compound]/(K_(d)+[compound]) where F is the fluorescenceintensity at a given compound concentration, F₀ is the fluorescenceintensity of the blank, and F_(max) is the maximum fluorescenceintensity.

NMR Spectroscopy

NMR experiments were performed on Bruker Avance III spectrometersequipped with a cryoprobe, operating at ¹H frequencies of 500 MHz and700 MHz. NMR samples contained 50 μM of [U-¹⁵N] RAGE tail and 10 μM ofthe test compound in 10 mM phosphate buffer [pH 7.0] and 5% d₆-DMSO. Allspectra were collected at 298 K, which yielded high quality NMR spectraof [U-¹⁵N] ctRAGE¹. We used a Watergate version of the ¹H{¹⁵N}— editedheteronuclear single quantum coherence (HSQC) experiment 14 recordedwith 64 transients as 512×64 complex points in proton and nitrogendimensions, respectively, apodized with a squared cosine-bell windowfunction and zero-filled to 1024×128 points prior to Fouriertransformation. The corresponding sweep widths were 12 and 35 ppm in the¹H and ¹⁵N dimensions, respectively. The spectra were processed by usingthe program TOPSPIN 2.1 (Bruker, Inc) and the program CARA¹⁵ was usedfor spectral analysis. Chemical shifts [U-¹⁵N] ctRAGE were assigned¹¹.To reassign the [U-¹⁵N] RAGE tail peaks that changed position due tocomplex formation we assumed minimum chemical shift changes¹⁶,calculated as ΔΩ=((ΔΩ_(HN))²+(0.25*ΔΩ_(N))²)^(11/14), where Ω_(NH) andΩ_(N) represent amide hydrogen and nitrogen chemical shifts,respectively. Peak intensity changes were calculated as:(I/I_(ref))_(free)−(I/I_(ref))complex, where I is an individual peakintensity and I_(ref) is the peak intensity of a glutamine at 7.45 ppmand 112.5 ppm in the proton and nitrogen dimensions, respectively, thatdoes not shift during titration.

Smooth Muscle Cell Migration Assay

Murine vascular smooth muscle cells (SMCs) were cultured from the aortasof 10-week old male mice using a modification of the procedure of Travoand Barret¹⁷. SMCs were cultured following an explant protocol inaccordance with institutional guidelines. Wild-type murine aorticvascular SMCs were isolated and used between passages 8 to 12. Migrationin response to the RAGE ligand CML-AGE (CML, 10 μg/ml) or a generaleffector, not a RAGE ligand, PDGF-BB, 10 ng/ml (R&D systems,Minneapolis, Minn., USA) was assessed with a wounding assay. Cells weregrown to confluence in 12-well plates and starved overnight. Thefollowing morning, serum free media was removed and compounds wereadded. Immediately following the addition of compounds, the monolayerwas wounded using a p200 pipette tip and the compounds were allowed toincubate for 1.5 h. Following this incubation, all compounds wereremoved and fresh media containing RAGE ligand or general effector,PDGF-BB, was added for 7 h. Cells were maintained at 37° C. and 5% CO₂.Images were obtained at TO and T7. Each image was measured and an areaingrowth of effective migrating cells was calculated. The SMC migrationassay data for representative compounds, Compounds 229 and 247, isdepicted in FIGS. 5a and 5b , respectively.

TABLE 4 Additional in vitro Assay Data for Exemplary Quinoline CompoundsCom- Fluorescent SMC migration Direct Binding pound Binding Assay, IC50to tail, # Assay, Kd (nM) (nM)** NMR (Y or N) Benchmark 203 3 84 Y 20824 99 Y 214 34 4 Y 215 27 460 Y 216 *** **** N 217 *** **** N 218 80 133Y 219 89 **** Y 220 22 300 Y 221 34 5000 Y 222 32 3200 Y 223 72 NT Y 22432 99 Y 225 122 44 Y 226 25 3 Y 227 10 **** Y 228 122 10 Y 229 3 0.2 Y230 *** **** N 231 47 18 Y 232 *** **** N 233 *** **** N 234 12 0.4 Y235 76 17 Y 236 56 0.1 Y 237 *** **** N 238 16 0.08 Y 239 13 **** Y 240*** **** (—) 241 11 **** Y 242 8 44 Y 243 *** **** (—) 244 54 **** Y 245*** **** (—) 246 *** **** (—) 247 2 1 Y 248 *** **** (—) 249 *** ****(—) 250 81 40 Y 251 168 **** Y 252 29 61 Y 253 1300 1200 Y 254 1340 2000Y 255 137 **** Y 256 5800 **** N 257 NT 1500 NT 258 NT 323 NT 259 NT**** NT 260 NT 14 NT 261 NT 1400 NT 262 NT 2900 NT **In SMC migrationassay, none of the compounds demonstrated inhibition of SMC migration inresponse to NON-ligand, PDGF ***No binding ****No inhibition or bad fitor inhibition out of range NT not tested

Example B3 Representative In Vivo Assays Methods and Materials

The effects of compounds described herein on an in vivo model of delayedtype hypersensitivity (DTH) can be determined using the followingsystem. Female CF-1 mice can be purchased from the Jackson Laboratories(Bar Harbor Me.) and after a period of at least 3 days acclimation inthe animal facility, mice can be sensitized over the left inguinal lymphnode with an emulsion (0.1 ml) containing methylated bovine serumalbumin (mBSA, Sigma, 25 mg/ml), NaCl (0.9%), dextran 5-40×10⁶ MW; 50mg/ml (Sigma), and Freunds' incomplete adjuvant (50%). On day 19 and 20after sensitization, mice may receive an intraperitoneal dose of acompound as described herein at 5 mg/kg/body weight mouse for a total offour doses. Control animals receive equal volumes of compound diluent,DMSO. Immediately following the final compound injection (4^(th) dose),mBSA (0.4 mg/ml; 0.050 ml) is injected into the left plantar hind paw.The paw is scored 16 hrs later by 2 investigators naive to theexperimental condition and according to the following criteria:1=absence of any inflammation; 2=slight rubor and edema; 3=moderaterubor and edema with skin wrinkles; 4=severe rubor and edema withoutskin wrinkles and 5=severe rubor and edema with toe spreading. See alsoHofmann et al. (1999, Cell 97:889-901), the entire content of which isincorporated herein in its entirety.

In Vivo Inflammation Assay

All animal procedures were approved by the Institutional Animal Care andUse Committees of New York University and performed in accordance withthe National Institutes of Health Animal Care Guidelines. In vivoinflammation model¹⁸ was used to test LSII compounds in delayed typehypersensitivity (DTH) assay. Female CF-1 mice, approximately 8 weeks ofage, were sensitized by subcutaneous injection over the right inguinallymph node of an emulsion (0.1 ml) containing methylated bovine serumalbumin (BSA) (mBSA, 25 mg/ml; NaCL, 0.9%; and dextran (5-40×10⁶ MW, 50mg/ml) and Freund's incomplete adjuvant (50%). Three weeks later, theright plantar hind paw was injected subcutaneously with mBSA (0.4 mg/ml;0.050 ml). Prior to the plantar paw injection, mice were pre-treatedwith the indicated LSII compounds (5 mg/kg po by gavage q 12 for fourdoses) or control vehicle, with last dose 14 h prior to the DTH scoringreadout. Equal volumes of vehicle were administered as control. Clinicalscoring of the foot pad was performed by investigators naïve to theexperimental conditions as follows: Score range is from 1-5 with1=completely normal foot pad with absence of any redness or swelling,through a range where 5=severe inflammation with massive swellingsufficient to prevent mouse from closing its toes together.

The representative compounds were tested in the DTH assay. Compounds 203and 208 were the benchmarks and Compounds 214, 226, and 229 were tested.The results are shown in FIG. 6.

From the foregoing description, various modifications and changes in thecompositions and methods of this invention will occur to those skilledin the art. All such modifications coming within the scope of theappended claims are intended to be included therein.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The chemical names of compounds of invention given in this applicationare generated using Open Eye Software's Lexichem naming tool, SymyxRenassance Software's Reaction Planner or MDL's ISIS Draw AutonomSoftware tool and not verified. Preferably, in the event ofinconsistency, the depicted structure governs.

REFERENCES

-   1) International Diabetes Federation. (2012) IDF Diabetes Atlas (5th    edn), International Diabetes Federation; Brussels, Belgium-   2) Patterson, C. C., et al. (2012) Trends in childhood type 1    diabetes incidence in Europe during 1989-2008: evidence of    non-uniformity over time in rates of increase. Diabetologia 55,    2142-2147-   3) Lipman, T. H., et al. (2013) Increasing Incidence of Type 1    Diabetes in Youth: Twenty years of the Philadelphia Pediatric    Diabetes Registry. Diabetes Care 36, 1597-1603-   4) Nathan D M, et al. (2009) Medical management of hyperglycemia in    type 2 diabetes: a consensus algorithm for the initiation and    adjustment of therapy: a consensus statement of the American    Diabetes Association and the European Association for the Study of    Diabetes. Diabetes Care 3: 193-203.-   5) (UKPDS), U.P.D.S.G. (1998) Intensive blood-glucose control with    sulphonylureas or insulin compared with conventional treatment and    risk of complications in patients with type 2 diabetes (UKPDS 33).    UK Prospective Diabetes Study (UKPDS) Group. Lancet, pp. 837-853-   6) The Diabetes Control and Complications Trial Research    Group (1993) The effect of intensive treatment of diabetes on the    development and progression of long-term complications in    insulin-dependent diabetes mellitus. The Diabetes Control and    Complications Trial Research Group. New Engl J Med, pp. 977-986-   7) Frye, E. B., et al. (1998) Role of the Maillard reaction in aging    of tissue proteins. Advanced glycation end product-dependent    increase in imidazolium cross-links in human lens proteins. J Biol    Chem 273, 18714-18719-   8) Yan, S. F., et al. (2009) Tempering the wrath of RAGE: an    emerging therapeutic strategy against diabetic complications,    neurodegeneration, and inflammation. Ann Med 41, 408-422-   9) Yan, S. F., et al. (2010) The RAGE axis: a fundamental mechanism    signaling danger to the vulnerable vasculature. Circ Res 106,    842-853-   10) Hudson, B. I., et al. (2008) Interaction of the RAGE cytoplasmic    domain with diaphanous-1 is required for ligand-stimulated cellular    migration through activation of Racl and Cdc42. J Biol Che283,    34457-34468-   11) Rai, V., et al. (2012) Signal transduction in receptor for    advanced glycation end products (RAGE): solution structure of    C-terminal rage (ctRAGE) and its binding to mDia1. J Biol Chem 287,    5133-5144-   12) Xu, Y., et al. (2010) Advanced glycation end product    (AGE)-receptor for AGE (RAGE) signaling and up-regulation of Egr-1    in hypoxic macrophages. J Biol Chem 285, 23233-23240-   13) Toure, F., et al (2012) Formin mDia1 mediates vascular    remodeling via integration of oxidative and signal transduction    pathways. Circ Res 110, 1279-1293.-   14). Cavanagh, J., Fairbrother, W. J., Palmer Iii, A. G., Rance, M.    & Skelton, N. J. Protein NMR Spectroscopy: Principles and Practice.    (Academic Press, 2007).-   15) Keller, R. L. J. The Computer Aided Resonance Assignment    Tutorial. (CANTINA Verlag, 2004).-   16). Farmer, B. T., 2nd et al. Localizing the NADP+ binding site on    the MurB enzyme by NMR. Nat. Struct. Biol. 3, 995-997 (1996).-   17). Travo, P., Barrett, G. & Burnstock, G. Differences in    proliferation of primary cultures of vascular smooth muscle cells    taken from male and female rats. Blood Vessels 17, 110-116 (1980).-   18). Hofmann, M. A. et al. RAGE mediates a novel proinflammatory    axis: a central cell surface receptor for S100/calgranulin    polypeptides. Cell 97, 889-901 (1999).

What is claimed is:
 1. A method for preventing, treating or amelioratingin a mammal a disease or condition that is causally related to RAGEactivity in vivo, which comprises administering to the mammal aneffective disease-treating or condition-treating amount of a compoundaccording to formula C-I:

wherein Cy is substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; L is a single bond, C₁-C₄ alkylenyl, —C(O)—,—S—, —S(O)—, or —S(O)₂—; R¹ is substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR², or —NR²R³; each R² and R³ is independently H,substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R²and R³ are joined together to form a substituted or unsubstitutedheterocycle; each R^(4a) is independently selected from OH, substitutedor unsubstituted alkyl, substituted or unsubstituted alkoxy, substitutedor unsubstituted acyl, substituted or unsubstituted acylamino,substituted or unsubstituted alkylamino, substituted or unsubstitutedalkythio, substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkylarylamino, substituted or unsubstituted amino,substituted or unsubstituted arylalkyl, sulfo, substituted sulfo,substituted sulfonyl, substituted sulfinyl, substituted sulfanyl,substituted or unsubstituted aminosulfonyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido,substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted dialkylamino, halo,nitro, and thiol; and R^(4b) is selected from H, OH, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted acyl, substituted or unsubstituted acylamino, substitutedor unsubstituted alkylamino, substituted or unsubstituted alkythio,substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkylarylamino, substituted or unsubstituted amino,substituted or unsubstituted arylalkyl, sulfo, substituted sulfo,substituted sulfonyl, substituted sulfinyl, substituted sulfanyl,substituted or unsubstituted aminosulfonyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido,substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted dialkylamino, halo,nitro, and thiol; the subscript n is 0, 1, 2, 3, or 4; or apharmaceutically acceptable salt, N-oxide, solvate or prodrug thereof;and stereoisomers, isotopic variants and tautomers thereof; providedthat the compound is other than


2. A compound according to formula C-I:

wherein Cy is substituted or unsubstituted aryl or substituted orunsubstituted heteroaryl; L is a single bond, C₁-C₄ alkylenyl, —C(O)—,—S—, —S(O)—, or —S(O)₂—; R¹ is substituted or unsubstituted C₁-C₆ alkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, —OR², or —NR²R³; each R² and R³ is independently H,substituted or unsubstituted C₁-C₆ alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl; R²and R³ are joined together to form a substituted or unsubstitutedheterocycle; each R^(4a) is independently selected from OH, substitutedor unsubstituted alkyl, substituted or unsubstituted alkoxy, substitutedor unsubstituted acyl, substituted or unsubstituted acylamino,substituted or unsubstituted alkylamino, substituted or unsubstitutedalkythio, substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkylarylamino, substituted or unsubstituted amino,substituted or unsubstituted arylalkyl, sulfo, substituted sulfo,substituted sulfonyl, substituted sulfinyl, substituted sulfanyl,substituted or unsubstituted aminosulfonyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido,substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted dialkylamino, halo,nitro, and thiol; and R^(4b) is selected from H, OH, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted acyl, substituted or unsubstituted acylamino, substitutedor unsubstituted alkylamino, substituted or unsubstituted alkythio,substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkylarylamino, substituted or unsubstituted amino,substituted or unsubstituted arylalkyl, sulfo, substituted sulfo,substituted sulfonyl, substituted sulfinyl, substituted sulfanyl,substituted or unsubstituted aminosulfonyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido,substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted dialkylamino, halo,nitro, and thiol; the subscript n is 0, 1, 2, 3, or 4; or apharmaceutically acceptable salt, N-oxide, solvate or prodrug thereof;and stereoisomers, isotopic variants and tautomers thereof; providedthat the compound is other than


3. The method according to claim 1 or the compound according to claim 2,wherein L is a single bond.
 4. The method according to claim 1 or thecompound according to claim 2, wherein L is —CH₂, —CH₂—CH₂—, or—CH₂—CH₂—CH₂—.
 5. The method according to claim 1 or the compoundaccording to claim 2, wherein L is —CH₂ or —C(Me)H—
 6. The methodaccording to claim 1 or the compound according to claim 2, wherein L is—C(O)—.
 7. The method according to claim 1 or the compound according toclaim 2, wherein L is —S(O)—, or —S(O)₂—.
 8. The method according toclaim 1 or the compound according to claim 2, wherein the compound isaccording to formula C-IIa, C-IIb, C-IIc, C-IId, or C-IIe:

wherein Cy, R¹, R^(4a), R^(4b), and n are as in claim
 1. 9. The methodor the compound according to any one of claims 1-8, wherein Cy issubstituted or unsubstituted aryl.
 10. The method or the compoundaccording to any one of claims 1-8, wherein Cy is substituted orunsubstituted phenyl or naphthyl.
 11. The method or the compoundaccording to any one of claims 1-8, wherein Cy is substituted orunsubstituted phenyl.
 12. The method or the compound according to anyone of claims 1-8, wherein Cy is substituted or unsubstitutedheteroaryl.
 13. The method or the compound according to any one ofclaims 1-8, wherein Cy is substituted or unsubstituted pyridyl,pyrimidinyl, or pyrazinyl.
 14. The method or the compound according toany one of claims 1-8, wherein Cy is substituted or unsubstituted2-pyridyl, 3-pyridyl, or 4-pyridyl.
 15. The method according to claim 1or the compound according to claim 2, wherein the compound is accordingto formula C-IIIa, C-IIIb, C-IIIc, C-IIId, or C-IIIe:

wherein R¹, R^(4a), R^(4b), and n are as in claim 1; each X and Y′ isindependently —CH—, or —N—; each R⁵ is independently selected from OH,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted acyl, substituted or unsubstitutedacylamino, substituted or unsubstituted alkylamino, substituted orunsubstituted alkythio, substituted or unsubstituted alkoxycarbonyl,substituted or unsubstituted alkylarylamino, substituted orunsubstituted amino, substituted or unsubstituted arylalkyl, sulfo,substituted sulfo, substituted sulfonyl, substituted sulfinyl,substituted sulfanyl, substituted or unsubstituted aminosulfonyl,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedarylsulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl,cyano, substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituteddialkylamino, halo, nitro, and thiol; and the subscript m is 0, 1, 2, 3,or
 4. 16. The method or the compound according to claim 15, wherein X isN.
 17. The method or the compound according to claim 15, wherein Y′ isN.
 18. The method or the compound according to any one of claims 1-2,wherein the compound is according to formula C-I:

wherein Cy is

R¹ is —OR², or —NR²R³; each R² and R³ is independently H, substituted orunsubstituted C₁-C₆ alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl; R² andR³ are joined together to form a substituted or unsubstitutedheterocycle; each R^(4a) is independently selected from OH, substitutedor unsubstituted alkyl, substituted or unsubstituted alkoxy, substitutedor unsubstituted acyl, substituted or unsubstituted acylamino,substituted or unsubstituted alkylamino, substituted or unsubstitutedalkythio, substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkylarylamino, substituted or unsubstituted amino,substituted or unsubstituted arylalkyl, sulfo, substituted sulfo,substituted sulfonyl, substituted sulfinyl, substituted sulfanyl,substituted or unsubstituted aminosulfonyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido,substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted dialkylamino, halo,nitro, and thiol; and R^(4b) is selected from H, OH, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted acyl, substituted or unsubstituted acylamino, substitutedor unsubstituted alkylamino, substituted or unsubstituted alkythio,substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkylarylamino, substituted or unsubstituted amino,substituted or unsubstituted arylalkyl, sulfo, substituted sulfo,substituted sulfonyl, substituted sulfinyl, substituted sulfanyl,substituted or unsubstituted aminosulfonyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido,substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted dialkylamino, halo,nitro, and thiol; the subscript n is 0, 1, 2, 3, or 4; each R⁵ isindependently selected from OH, substituted or unsubstituted alkyl,substituted or unsubstituted alkoxy, substituted or unsubstituted acyl,substituted or unsubstituted acylamino, substituted or unsubstitutedalkylamino, substituted or unsubstituted alkythio, substituted orunsubstituted alkoxycarbonyl, substituted or unsubstitutedalkylarylamino, substituted or unsubstituted amino, substituted orunsubstituted arylalkyl, sulfo, substituted sulfo, substituted sulfonyl,substituted sulfinyl, substituted sulfanyl, substituted or unsubstitutedaminosulfonyl, substituted or unsubstituted alkylsulfonyl, substitutedor unsubstituted arylsulfonyl, azido, substituted or unsubstitutedcarbamoyl, carboxyl, cyano, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted dialkylamino, halo, nitro, and thiol; R⁶ is substitutedor unsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl; and a) L is a single bond, —CH₂—, —C(Me)H—, or —CH₂—CH₂—; Xis CH, Y′ is C—NH—C(O)—R⁶; and m is 0, 1, 2, 3, or 4; b) L is —C(O)—; Y′is C—NH—C(O)—R⁶; and m is 1, 2, 3, or 4; c) L is a single bond, —CH₂—,—C(Me)H—, or —CH₂—CH₂—, or —C(O)—; X is N, Y′ is C—NH—C(O)—R⁶; and m is0, 1, 2, 3, or 4; d) L is —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or —C(O)—; X isN, Y′ is CH; and m is 0, 1, 2, 3, or 4; e) L is a single bond, or—C(O)—; X is N, Y′ is CH; and m is 1, 2, 3, or 4; f) L is —CH₂—,—C(Me)H—, or —CH₂—CH₂—, or —C(O)—; X is CH, Y′ is N; and m is 0, 1, 2,3, or 4; g) L is a single bond, or —C(O)—; X is CH, Y′ is N; and m is 1,2, 3, or 4; h) L is —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or —C(O)—; Cy is

and m is 0, 1, 2, 3, or 4; j) L is a single bond, or —C(O)—; Cy is

and m is 1, 2, 3, or 4; or k) L is —S(O)— or —S(O)₂—; and m is 0, 1, 2,3, or 4; or a pharmaceutically acceptable salt, N-oxide, solvate orprodrug thereof; and stereoisomers, isotopic variants and tautomersthereof.
 19. The method or the compound according to claim 18, whereinthe compound is according to formula C-IVa, C-IVb, C-IVc, C-IVd, orC-IVe:

wherein R¹, R^(4a), R^(4b), and n are as in claim 18; and R⁶ issubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl.
 20. The method or the compound according toclaim 18, wherein the compound is according to formula C-Va, C-Vb, C-Vc,C-Vd, or C-Ve:

wherein R¹, R^(4a), R^(4b), and n are as in claim
 18. 21. The method orthe compound according to claim 18, wherein the compound is according toformula C-VIa, C-VIb, C-VIc, C-VId, or C-VIe:

wherein R¹, R^(4a), R^(4b), and n are as in claim
 18. 22. The method orthe compound according to claim 18, wherein the compound is according toformula C-VIIa, C-VIIb, C-VIIc, C-VIId, or Vile:

wherein R¹, R^(4a), R^(4b), and n are as in claim 18; and R⁶ issubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted aryl, and substituted orunsubstituted heteroaryl.
 23. The method or the compound according toany one of claims 1-22, wherein R^(4b) is halo, CN, substituted orunsubstituted alkyl, or substituted or unsubstituted alkoxy.
 24. Themethod or the compound according to any one of claims 1-22, whereinR^(4b) is F, Cl, CN, Me, Et, i-Pr, OMe, OEt, or CF₃.
 25. The method orthe compound according to any one of claims 1-22, wherein R^(4b) is H.26. The method or the compound according to claim 18, wherein thecompound is according to formula C-VIIIa, C-VIIIb, C-VIIIc, C-VIIId, orC-VIIIe:

wherein R¹, R^(4a), and n are as in claim 18; and R⁶ is substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.
 27. The method or the compound according to claim 18,wherein the compound is according to formula C-IXa, C-IXb, C-IXc, C-IXd,or C-IXe:

wherein R¹, R^(4a), and n are as in claim 18; and R⁶ is substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.
 28. The method or the compound according to claim 18,wherein the compound is according to formula C-Xa, C-Xb, C-Xc, C-Xd, orC-Xe:

wherein R¹, R^(4a), and n are as in claim
 18. 29. The method or thecompound according to claim 18, wherein the compound is according toformula C-XIa, C-XIb, C-XIc, C-XId, or C-XIe:

wherein R¹, R^(4a), and n are as in claim
 18. 30. The method or thecompound according to claim 18, wherein the compound is according toformula C-XIIa, C-XIIb, C-XIIc, C-XIId, or C-XIIe:

wherein R¹ is as in claim 18; and R⁶ is substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl.
 31. Themethod or the compound according to claim 18, wherein the compound isaccording to formula C-XIIIa, C-XIIIb, C-XIIIc, C-XIIId, or C-XIIIe:

wherein R¹ is as in claim 18; and R⁶ is substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted aryl, and substituted or unsubstituted heteroaryl.
 32. Themethod or the compound according to claim 18, wherein the compound isaccording to formula C-XIVa, C-XIVb, C-XIVc, C-XIVd, or C-XIVe:

wherein R¹ is as in claim
 18. 33. The method or the compound accordingto claim 18, wherein the compound is according to formula C-XVa, C-XVb,C-XIVc, C-XIVd, or C-XVe:

wherein R¹ is as in claim
 18. 34. The method or the compound accordingto any one of claims 1-33, wherein R¹ is substituted or unsubstitutedC₁-C₆ alkyl.
 35. The method or the compound according to any one ofclaims 1-33, wherein R¹ is Me, Et, i-Pr, n-Pr, n-Bu, or t-Bu.
 36. Themethod or the compound according to any one of claims 1-33, wherein R¹is —OR²; and R² is H, substituted or unsubstituted C₁-C₆ alkyl, orsubstituted or unsubstituted cycloalkyl.
 37. The method or the compoundaccording to any one of claims 1-33, wherein R¹ is OMe, OEt, or O-i-Pr.38. The method or the compound according to any one of claims 1-33,wherein R¹ is —NR²R³; and each R² and R³ is independently H, substitutedor unsubstituted C₁-C₆ alkyl, or substituted or unsubstitutedcycloalkyl.
 39. The method or the compound according to any one ofclaims 1-33, wherein R¹ is —NR²R³; and each R² and R³ is independentlyH, Me, Et, i-Pr, n-Pr, n-Bu, or t-Bu.
 40. The method or the compoundaccording to any one of claims 1-33 wherein R¹ is —NR²R³; and R² is H orMe; and R³ is Me, Et, i-Pr, n-Pr, n-Bu, or t-Bu.
 41. The method or thecompound according to any one of claims 1-33, wherein R¹ is —NR²R³; andR² is H or Me; and R³ is Et, i-Pr, n-Pr, n-Bu, or t-Bu; each of which issubstituted with hydroxyl, alkoxy, amino, alkylamino, or dialkylamino.42. The method or the compound according to any one of claims 1-33,wherein R¹ is —NR²R³; and R² and R³ are joined together to form asubstituted or unsubstituted heterocycle.
 43. The method or the compoundaccording to any one of claims 1-33, wherein R¹ is pyrrolidin-1-yl,piperidin-1-yl, piperizin-1-yl, or morpholin-1-yl.
 44. The method or thecompound according to any one of claims 1-2, wherein the compound isaccording to formula C-I:

wherein Cy is

R¹ is

Y is CH₂, NH, or O; each R^(4a) is independently selected from OH,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted acyl, substituted or unsubstitutedacylamino, substituted or unsubstituted alkylamino, substituted orunsubstituted alkythio, substituted or unsubstituted alkoxycarbonyl,substituted or unsubstituted alkylarylamino, substituted orunsubstituted amino, substituted or unsubstituted arylalkyl, sulfo,substituted sulfo, substituted sulfonyl, substituted sulfinyl,substituted sulfanyl, substituted or unsubstituted aminosulfonyl,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedarylsulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl,cyano, substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituteddialkylamino, halo, nitro, and thiol; and R^(4b) is selected from H, OH,substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy,substituted or unsubstituted acyl, substituted or unsubstitutedacylamino, substituted or unsubstituted alkylamino, substituted orunsubstituted alkythio, substituted or unsubstituted alkoxycarbonyl,substituted or unsubstituted alkylarylamino, substituted orunsubstituted amino, substituted or unsubstituted arylalkyl, sulfo,substituted sulfo, substituted sulfonyl, substituted sulfinyl,substituted sulfanyl, substituted or unsubstituted aminosulfonyl,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedarylsulfonyl, azido, substituted or unsubstituted carbamoyl, carboxyl,cyano, substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituteddialkylamino, halo, nitro, and thiol; the subscript n is 0, 1, 2, 3, or4; each R⁵ is independently selected from OH, substituted orunsubstituted alkyl, substituted or unsubstituted alkoxy, substituted orunsubstituted acyl, substituted or unsubstituted acylamino, substitutedor unsubstituted alkylamino, substituted or unsubstituted alkythio,substituted or unsubstituted alkoxycarbonyl, substituted orunsubstituted alkylarylamino, substituted or unsubstituted amino,substituted or unsubstituted arylalkyl, sulfo, substituted sulfo,substituted sulfonyl, substituted sulfinyl, substituted sulfanyl,substituted or unsubstituted aminosulfonyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted arylsulfonyl, azido,substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted dialkylamino, halo,nitro, and thiol; R⁶ is substituted or unsubstituted alkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl; and a) L is a single bond,—CH₂—, —C(Me)H—, or —CH₂—CH₂—; X is CH, Y′ is C—NH—C(O)—R⁶; and m is 0,1, 2, 3, or 4; b) L is —C(O)—; Y′ is C—NH—C(O)—R⁶; and m is 1, 2, 3, or4; c) L is a single bond, —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or —C(O)—; X isN, Y′ is C—NH—C(O)—R⁶; and m is 0, 1, 2, 3, or 4; d) L is —CH₂—,—C(Me)H—, or —CH₂—CH₂—, or —C(O)—; X is N, Y′ is CH; and m is 0, 1, 2,3, or 4; e) L is a single bond, or —C(O)—; X is N, Y′ is CH; and m is 1,2, 3, or 4; f) L is —CH₂—, —C(Me)H—, or —CH₂—CH₂—, or —C(O)—; X is CH,Y′ is N; and m is 0, 1, 2, 3, or 4; g) L is a single bond, or —C(O)—; Xis CH, Y′ is N; and m is 1, 2, 3, or 4; h) L is —CH₂—, —C(Me)H—, or—CH₂—CH₂—, or —C(O)—; Cy is

and m is 0, 1, 2, 3, or 4; or j) L is a single bond, or —C(O)—; Cy is

and m is 1, 2, 3, or 4; or a pharmaceutically acceptable salt, N-oxide,solvate or prodrug thereof; and stereoisomers, isotopic variants andtautomers thereof.
 45. The method or the compound according to claim 44,wherein R^(4b) is halo, CN, substituted or unsubstituted alkyl, orsubstituted or unsubstituted alkoxy.
 46. The method or the compoundaccording to claim 44, wherein R^(4b) is F, Cl, CN, Me, Et, i-Pr, OMe,OEt, or CF₃.
 47. The method or the compound according to claim 44,wherein R^(4b) is H.
 48. The method or the compound according to claim44, wherein the compound is according to formula C-XVIa, C-XVIb, C-XVIc,C-XVId, or C-XVIe:

wherein R⁶ is substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl; and Y is CH₂, NH, or O.
 49. Themethod or the compound according to claim 44, wherein the compound isaccording to formula C-XVIIa, C-XVIIb, C-XVIIc, C-XVIId, or C-XVIIe:

wherein R⁶ is substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl; and Y is CH₂, NH, or O.
 50. Themethod or the compound according to claim 44, wherein the compound isaccording to formula C-XVIIIa, C-XVIIIb, C-XVIIIc, C-XVIIId, orC-XVIIIe:

wherein Y is CH₂, NH, or O.
 51. The method or the compound according toclaim 44, wherein the compound is according to formula C-XIXa, C-XIXb,C-XIXc, C-XIXd, or C-XIXe:

wherein Y is CH₂, NH, or O.
 52. The method or the compound according toclaim 44, wherein the compound is according to formula C-XXa, C-XXb,C-XXc, C-XXd, or C-XXe:

wherein Y is CH₂, NH, or O.
 53. The method or the compound according toany one of claims 1-29, and 34-52, wherein n is 1, 2, 3, or
 4. 54. Themethod or the compound according to any one of claims 1-29, and 34-52,wherein n is 1 or
 2. 55. The method or the compound according to any oneof claims 1-29, and 34-52, wherein n is
 1. 56. The method or thecompound according to any one of claims 1-29, and 34-55, wherein eachR^(4a) is independently selected from halo, CN, substituted orunsubstituted alkyl, and substituted or unsubstituted alkoxy.
 57. Themethod or the compound according to any one of claims 1-29, and 34-55,wherein each R^(4a) is independently selected from F, Cl, CN, Me, Et,i-Pr, OMe, OEt, and CF₃.
 58. The method or the compound according to anyone of claims 1-29, and 34-52, wherein n is
 0. 59. The method or thecompound according to any one of claims 15-58, wherein m is 1, 2, 3, or4.
 60. The method or the compound according to any one of claims 15-58,wherein m is 1 or
 2. 61. The method or the compound according to any oneof claims 15-58, wherein m is
 1. 62. The method according to any one ofclaims 15-61, wherein each R⁵ is independently selected from halo, CN,substituted or unsubstituted alkyl, substituted or unsubstituted amino,substituted or unsubstituted acylamino, and substituted or unsubstitutedalkoxy.
 63. The method or the compound according to any one of claims15-61, wherein each R⁵ is independently selected from F, Cl, CN, Me, Et,i-Pr, OMe, OEt, —NH—C(O)R⁶, and CF₃; and R⁶ is substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.
 64. The method or the compound according to any one ofclaims 15-58, wherein m is 1; R⁵ is —NH—C(O)R⁶; and R⁶ is substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.
 65. Themethod or the compound according to any one of claims 15-58, wherein mis 1; R⁵ is —NH—C(O)R⁶; and R⁶ is Me, Et, i-Pr, n-Pr, n-Bu, t-Bu,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or Ph.
 66. The methodor the compound according to any one of claims 1-2, wherein the compoundis according to formula C-XVIb, C-XVId, C-XVIe, C-XVIIa, C-XVIIb,C-XVIIc, C-XVIId, C-XVIIe, C-XVIIIb, C-XVIIId, C-XVIIIe, C-XIXb, C-XIXd,C-XIXe, C-XXb, C-XXd, or C-XXe; and m is
 0. 67. The method or thecompound according to any one of claims 44-66, wherein Y is CH₂.
 68. Themethod or the compound according to any one of claims 44-66, wherein Yis N.
 69. The method or the compound according to any one of claims44-66, wherein Y is O.
 70. The method or the compound according to anyone of 1-69, wherein R⁶, when present, is substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.
 71. The method or the compoundaccording to any one of 1-69, wherein R⁶, when present, is Me, Et, i-Pr,n-Pr, n-Bu, t-Bu, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, orPh.
 72. The method or the compound according to any one of 1-69, whereinR⁶, when present, is Me, or Et.
 73. The method or the compound accordingto any one of 1-69, wherein R⁶, when present, is Me.
 74. The methodaccording to claim 1 or the compound according to claim 2, wherein thecompound is any one of compounds listed in Table 1 or Table 2; or thecompound is selected from the group consisting of:2-(4-Acetamidophenyl)-N-(2-(dimethylamino)ethyl)quinoline-4-carboxamide,N-(4-(4-(Morpholine-4-carbonyl)quinolin-2-yl)phenyl)acetamide,8-Chloro-N-cyclopropyl-2-(pyridin-2-yl)quinoline-4-carboxamide;(6-Chloro-2-(pyridin-3-yl)quinolin-4-yl)(4-(methylsulfonyl)piperazin-1-yl)methanone,6-Methyl-N-(5-methylisoxazol-3-yl)-2-(pyridin-3-yl)quinoline-4-carboxamide,N-(4-(8-Chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)phenyl)acetamide,N-(5-(8-Chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)pyridin-2-yl)acetamide,N-(6-(8-Chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)pyridin-3-yl)acetamide,N-(4-(6-Chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)phenyl)acetamide,N-(5-(6-Chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)pyridin-2-yl)acetamide,N-(6-(6-Chloro-4-(morpholine-4-carbonyl)quinolin-2-yl)pyridin-3-yl)acetamide,N-(4-(4-Morpholinoquinolin-2-yl)phenyl)acetamide,N-(4-(4-(Morpholinomethyl)quinolin-2-yl)phenyl)acetamide,N-(6-(4-(Morpholinomethyl)quinolin-2-yl)pyridin-3-yl)acetamide,N-(4-(8-Chloro-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide,N-(6-(8-Chloro-4-(morpholinomethyl)quinolin-2-yl)pyridin-3-yl)acetamide,N-(4-(4-(1-Morpholinoethyl)quinolin-2-yl)phenyl)acetamide;(N-(2-fluoro-4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide);(N-(2-chloro-4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide);(N-(2-methoxy-4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide);(N-(2-hydroxy-4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide);N-(2-cyano-4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide;(2-hydroxy-N-(4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide);(2-methoxy-N-(4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide);(2-amino-N-(4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide);(2-acetamido-N-(4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide);(N-(4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)propionamide);(N-(4-(4-(morpholinomethyl)quinolin-2-yl)phenyl)isobutyramide);(N-(4-(7-fluoro-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide);(N-(4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide);(N-(4-(7-methyl-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide);(N-(4-(7-methoxy-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide);N-(4-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide;2-(4-acetamidophenyl)-4-(morpholinomethyl)quinoline-7-carboxamide;(N-(4-(4-(((2-hydroxyethyl)amino)methyl)quinolin-2-yl)phenyl)acetamide);(N-(4-(4-(((2-hydroxyethyl)(methyl)amino)methyl)quinolin-2-yl)phenyl)acetamide);N-(4-(4-(((2-methoxyethyl)amino)methyl)quinolin-2-yl)phenyl)acetamide);N-(4-(4-(((2-methoxyethyl)(methyl)amino)methyl)quinolin-2-yl)phenyl)acetamide;(N-(4-(4-((propylamino)methyl)quinolin-2-yl)phenyl)acetamide);N-(4-(4-((methyl(propyl)amino)methyl)quinolin-2-yl)phenyl)acetamide;N-(4-(4-((butylamino)methyl)quinolin-2-yl)phenyl)acetamide;(N-(4-(4-((butyl(methyl)amino)methyl)quinolin-2-yl)phenyl)acetamide);(N-(4-(4-(((2-(dimethylamino)ethyl)amino)methyl)quinolin-2-yl)phenyl)acetamide);(N-(4-(4-(((2-(dimethylamino)ethyl)(methyl)amino)methyl)quinolin-2-yl)phenyl)acetamide);(N-(4-(4-(((2-(methylamino)ethyl)amino)methyl)quinolin-2-yl)phenyl)acetamide);(N-(4-(4-((methyl(2-(methylamino)ethyl)amino)methyl)quinolin-2-yl)phenyl)acetamide);N-(4-(4-(3-morpholinopropyl)quinolin-2-yl)phenyl)acetamide; (tert-butyl4-((2-(4-acetamidophenyl)quinolin-4-yl)methyl)piperazine-1-carboxylate);(N-(4-(4-((4-methylpiperazin-1-yl)methyl)quinolin-2-yl)phenyl)acetamide);(N-(4-(4-((4-acetylpiperazin-1-yl)methyl)quinolin-2-yl)phenyl)acetamide);(N-(4-(4-(piperidin-1-ylmethyl)quinolin-2-yl)phenyl)acetamide);4-((2-(2-methyl-1H-benzo[d]imidazol-6-yl)quinolin-4-yl)methyl)morpholine;(2-methyl-6-(4-(morpholinomethyl)quinolin-2-yl)benzo [d]oxazole);N-(2-fluoro-4-(7-fluoro-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide;N-(2-chloro-4-(7-fluoro-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide;N-(2-cyano-4-(7-fluoro-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide;N-(4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)-2-fluorophenyl)acetamide;N-(2-chloro-4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide;N-(4-(7-chloro-4-(morpholinomethyl)quinolin-2-yl)-2-cyanophenyl)acetamide;N-(2-fluoro-4-(7-methoxy-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide;N-(2-chloro-4-(7-methoxy-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide;N-(2-cyano-4-(7-methoxy-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide;N-(4-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)-2-fluorophenyl)acetamide;N-(2-chloro-4-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide;N-(2-cyano-4-(7-cyano-4-(morpholinomethyl)quinolin-2-yl)phenyl)acetamide;andN-(4-(7-ethoxy-4-(morpholinomethyl)quinolin-2-yl)-2-fluorophenyl)acetamide.75. A pharmaceutical composition comprising the compound according toany one of claims 1-74.
 76. The method of claim 1, wherein the diseaseor condition is selected diabetes and its complications, impaired woundhealing, peripheral vascular disease and associated complications,obesity, Alzheimer's disease, cancers, arthritis, nephropathy, acute andchronic inflammation, retinopathy, atherosclerosis, cardiovasculardisease erectile dysfunction, tumor invasion and metastases, neuropathy,cardio- and cerebrovascular ischemia/reperfusion injury, heart attack,stroke, myocardial infarction, ischemic cardiomyopathy, renal ischemia,sepsis, pneumonia, infection, liver injury, liver damage, Amyotrophiclateral sclerosis, neuropathy infection, allergy, asthma, organ damagefrom pollutants, amyloidoses asthma, pollution-associated tissue damage,skin disorders, colitis, skin aging, lupus, and others.
 77. The methodof claim 1, wherein the disease or condition is diabetes and diabetesassociated complication.
 78. The method of claim 1, wherein the diseaseor condition is inflammation.
 79. The method of claim 1, wherein thedisease or condition is atherosclerosis.
 80. The method of claim 1,wherein the disease or condition is arthritis.
 81. The method of claim1, wherein the disease or condition is rheumatoid arthritis.
 82. Themethod of claim 1, wherein the disease or condition isneurodegeneration.
 83. The method of claim 1, wherein the disease orcondition is obesity.
 84. The method of claim 1, wherein the disease orcondition is sepsis or infection.
 85. The method of claim 1, wherein thedisease or condition is pneumonia.
 86. The method of claim 1, whereinthe disease or condition is liver injury or liver damage.
 87. The methodof claim 1, wherein the disease or condition is amyloidosis.
 88. Themethod of claim 1, wherein the disease or condition isischemia/reperfusion injury.
 89. The method of claim 1, wherein thedisease or condition is heart attack or stroke.
 90. The method of claim1, wherein the disease or condition is impaired wound healing.
 91. Themethod of claim 1, wherein the disease or condition is peripheralvascular disease.
 92. The method of claim 1, wherein the disease orcondition is colitis.